This research is being done to find out the safety of propranolol and, identify the maximum tolerated dose of propranolol that can be administered in combination with pembrolizumab in patients with unresectable stage III and stage IV melanoma. This study will evaluate this novel combination of pembrolizumab and propranolol to see what effect it may have on how your cancer responds to the treatment combination.

Phase II*propranolol twice a day.*pembrolizumab by an infusion every 3 weeks.*May receive treatment with pembrolizumab and propranolol for up to24 months from the time they began treatment with the combination.Procedures to be done:. A medical history  A physical exam ECOG Performance Status Perceived Stress Scale questionnaire An assessment of tumor by scan. Scans may include:o Computed tomography (CT), with or without contrast. o Magnetic resonance imaging (MRI) or head CT with IV contrast  Blood tests:o Approximately 2 tablespoons for routine testing, such as a complete blood count and acomprehensive metabolic panel Pregnancy test Urinalysis Electrocardiogram A sample of tumor from a previous biopsy or sample taken Phase 1 portion of the study, these evaluations/tests will also occur on Day 8 of Cycle 1 Review concomitant medications. Physical Exams ECOG Performance Status Perceived Stress Scale questionnaire Blood tests:o Every 3 weekso At 3 weeks and 6 months or discontinuation of treatment (whichever comes sooner) and atdisease progressiono Every 3 weeks: Approximately 1 tablespoon for tests that monitor your blood sugar levelsand thyroid functiono Every week for the first 6 weeks then every cycle for another 6 weeks Assessment of cancer by CT or MRI. These assessments will be performed every 12 weeks(± 14 days). The first assessment will be after completing Cycle 4. If their cancer is found to be improving,repeat the CT and MRI scans in about 12 weeks. EKG: Once treatment begins, this will be done every cycle prior to receiving pembrolizumab for the first 5 cycles. Adverse events Tumor Biopsy: A tumor biopsy (only in phase II) will be obtained at the 12 weeks after initiation oftreatment.Tumor biopsy will be optional for phase II patients..Safety Follow-Up:After all study treatment has stopped, end of treatmentvisit, which will be approximately 30 days after their last dose of study drug or before starting a newtreatment Medical History:  Concomitant medications complete physical examination ECOG Performance Status Perceived Stress Scale assessment Adverse events Survival status Blood tests:o Follow- Up Phase3 Month and 6 Month Follow- up After Treatment blood collected.The following assessments will be performed at 3 months and 6 months after the safety follow-up visit.Review concomitant medications Physical examination ECOG Performance Status Adverse events Survival Status Blood tests: CT of chest, abdomen and pelvis, or other areas as needed Long Term Survival Follow- Up:After your 3 month and 6 month follow up visits or if they progress, will be contacted every 6 months (±30 days)

Part 1 (Phase Ib): To determine the safety and ability for subjects to tolerate APG-115 when combined with pembrolizumab, as well as the maximum tolerated dose in subjects with metastatic melanomas or solid tumors.Part 2 (Phase II): To determine the overall response rate of APG-115 when combined with pembrolizumab in the treatment of patients with unresectable or metastatic melanomas. To assess APG-115 as a monotherapy in patients with unresectable or metastatic melanomas and MPNST cohorts only.

If you are eligible and agree to receive the study drug combination, you will need to come to the study site at various times to have procedures done. These procedures may include collection of vital signs, blood andurine samples, electrocardiogram, physical exam, tumor biopsy, imagingscans, and x-ray. At each visit, you will be asked about your current medicines, including over-the-counter medications, and about any symptoms or side effects you might be having. You will receive the study drug orally on Days 1, 3, 5, 7, 9, 11, 13 of every 21-day cycle. Pembrolizumab is given as a 30-minute intravenous (IV – through a needle into a vein) infusion on Day 1 of every 21-day cycle.

The purpose of this study is to test the efficacy of Daromun neoadjuvant treatment followed by surgery and adjuvant therapy to improve in a statistically significant manner the recurrence-free survival (RFS) of Stage IIIB/C melanoma patients with respect to the standard of care (surgery and adjuvant therapy)

•Blood collection for laboratory tests•CT/MRI/PET/CT scans•ECG•Take study drug•Tumor assessment