Denosumab + PD-1 in Subjects With Stage III/ IV Melanoma

Inclusion Criteria

• Signed written informed consent and HIPAA authorization for release of personal health information.
• Age ≥ 18 years at the time of consent.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
• Histologically confirmed melanoma of cutaneous or mucosal primary; (e.g. sinus, vagina, anus, gastrointestinal tract); metastatic melanomas from unknown primary are allowed because melanoma of unknown primary is biologically similar to cutaneous melanomas.
• AJCC stage III/IV unresectable (or resectable) disease. Both should be measurable by RECIST v1.1 criteria. Patients with resectable bulky stage IIIB, state IIIC or stage IIID melanoma (≥2-cm in shortest diameter for lymph nodes infiltrated by tumor and ≥2-cm in longest diameter for non-lymph nodes infiltrated by tumor) can also be entered into the study at the discretion of the Principal Investigator.
• Must have available and consent to collect archived tumor blocks from previous surgeries confirming or treating metastatic disease (e.g. radical lymph node dissection); if not available they can be enrolled into the trial, if they consent to have a tumor biopsy before treatment initiation.
• Must agree to undergo one on-treatment biopsy on week 4of the study; the biopsy at week 16 is optional.
• Must agree to have 100 mL blood drawn for study purposes on week 1 , day 20+or-2 (week 4), week 16, week 28, week 40 and end of treatment.
• Demonstrate adequate organ function, as listed below; all screening labs are to be obtained within 21 days prior to registration.
• Hemoglobin ≥ 10 g/dL without transfusion or erythropoietin dependency (within 7 days of assessment)
• Absolute Neutrophil Count (ANC) ≥ 1,500/mm3
• Absolute Lymphocyte Count (ALC) ≥ 1,000/mm3
• Platelets≥ 100,000/mm3
• Serum Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5 × upper limits of normal (ULN) OR
• ≥ 60 mL/min using the Cockcroft-Gault formula for subjects with creatinine levels > 1.5 × ULN
• Serum Total Bilirubin ≤ 1.5 × ULN or ≤ 2 × ULN for subjects with Gilbert's Syndrome
• Aspartate aminotransferase (AST) ≤ 2.5 × ULN OR 1 year) of costimulation with PD-1 inhibitors may be the reason for cancer recurrence and NOT primary resistance of PD-1 inhibitors.
• any side effects that may have occurred during the previous exposure to PD-1 inhibitors are not serious (i.e. grade 1 or 2 by CTCAE version 5.0 criteria).

Exclusion Criteria

• History of prior malignancy, with the exception of the following:
• Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of the cervix,
• Prior history of prostate, provided that patient is not under active systemic treatment other than hormonal therapy and with documented undetectable prostate specific antigen (PSA < 0.2 ng/mL),
• Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) provided patient has isolated lymphocytosis (Rai stage O), and does not require systemic treatment [for "B" symptoms, Richter's transformation, lymphocyte doubling time (< 6 months), lymphadenopathy or hepatosplenomegaly],
• Lymphoma or any type or hairy-cell leukemia, provided patient is not on an active systemic treatment and is in complete remission, as evidenced by Positron Emission Tomography (PET)/CT scans and bone marrow biopsies for at least 3 months,
• History of other malignancy, provided patient has completed therapy, or does not require therapy, and is free of disease for ≥ 2 years. If patient has had other malignancy within the last 2 years from which he/she may have been completely cured by surgery alone, or does not require any treatment other than observation at the specialist's discretion, he/she may considered to be enrolled on condition that the risk of development of recurrent or distant metastatic disease based on the American Joint Committee in Cancer (AJCC) staging system is less than 30% in 3 years from the original diagno