STUDY OBJECTIVES~Co-primary Objectives~Assess the mechanistic (immune-mediated and/or direct antitumor effect) and pharmacodynamics effect (tissue saturation studies) of denosumab alone (i.e., after three loading doses of denosumab are given on day 1,8 and 22) in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve cutaneous melanoma (stage III/IV) by performing translational research on peripheral blood and tumor biopsy samples collected at baseline and after third loading dose of Denosumab.~Assess the immune-mediated and direct antitumor effect of denosumab in combination with anti- PD-1 agent in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve cutaneous melanoma (AJCC stage III/IV) by performing translational research on peripheral blood and tumor biopsy samples collected at weeks 16, 28 and 40 of the study and comparing the results with those from baseline and after third loading dose of Denosumab.~Secondary Objectives~Assess the safety of the denosumab-anti-PD-1 agent combination in unresectable (resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve melanoma (AJCC stage III/IV) by NCI-CTCAE v.5.0.~Determine antitumor response by RECIST v1.1 criteria of the denosumab-anti- PD-1 agent combination at 16 weeks in patients with unresectable (resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve melanoma (AJCC stage III/IV).~Determine the 1-year OS rate of the Denosumab-anti-PD-1 agent combination in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naïve melanoma (AJCC stage III/IV).~Determine the 6-month PFS rate of the denosumab-anti-PD-1 agent combination in patients with unresectable (or resectable) stage III or distant metastatic PD-1/PD-L1 inhibitor-naive melanoma (AJCC stage III/IV).~Endpoints Co-primary Endpoints~The immune-mediated mechanism of action of denosumab alone will be evaluated in blood and tumor samples collected at baseline and after third loading dose of denosumab. Multiparameter flow cytometry and ELISA assays will be performed on peripheral blood/serum samples as outlined above in section 1.10.1 Tumor biopsy samples will be evaluated by IHC and IF studies as outlined above in section 1.10.2 (See referenced sections for assay details. The investigators will estimate differences after 3 weeks of denosumab treatment versus baseline).~The immune-mediated mechanism of action of denosumab combined with anti-PD-1 agent will be evaluated in blood and tumor samples collected at weeks 16, 28 and 40 of the study. Multi-parameter flow cytometry and ELISA assays will be performed on peripheral blood/serum samples collected at weeks 16, 28 and 40 as outlined above in section 1.10.1. Tumor biopsy samples obtained at week 16 will be evaluated by IHC and IF studies as outlined above in section 1.10.2 (See referenced sections for assay details. The investigators will describe differences in immunomodulatory/antitumor effects observed with denosumab therapy with later immunomodulatory/antitumor effects observed after the addition of an anti PD-1 agent to denosumab).~Secondary Endpoints~AEs experienced by patients receiving denosumab-anti- PD-1 agent will be assessed per NCI-CTCAE v.5.0.~The overall RR (CR + PR) at 16 weeks will assessed based on RECIST v1.1 criteria.~Overall Survival (OS) rate at 1-year is defined as the time from day 1 of study treatment until death as a result of any cause within one year of initiating study treatment.~Progression Free Survival (PFS) rate at 6 months is defined as the time from day 1 of treatment until disease progression or death status measured 6 months after initiating study treatment. Progression events will be defined per RECIST v1.1 criteria.~Procedures~Subjects in this trial will be given denosumab, 120 mg s.c. q4 weeks, starting on day 1 of study treatment. Additional loading doses of Denosumab will be administered on day 8 and day 22 ( after Amendment 1). Nivolumab, 480 mg will be administered intravenously (IV) every 4 weeks and initiated 21 days after the first dose of Denosumab is given. In subjects enrolled prior to Amendment 1 Pembrolizumab, 200 mg will be administered intravenously (IV) every 3 weeks and initiated 21 days after the first dose of denosumab is given. Combination therapy with both agents will continue as long as subjects benefit from therapy for up to 1 year. Study therapy will be discontinued for intolerable toxicity, disease progression or for other reasons at the discretion of the investigator. If subjects are not withdrawn prematurely then their last dose of study medications will be administered approximately 49 weeks after denosumab was initiated.
This is a multicenter open-label, single-arm, phase II study designed to investigate the pharmacodynamic and antitumor effects of denosumab alone and in combination with an anti-PD1 agent (pembrolizumab or nivolumab) in patients with unresectable PD-1/PD-L1 inhibitor-naïve regional and distant metastatic melanoma (AJCC stage III/IV). The pharmacodynamic and antitumor effects will be investigated by performing translational research on peripheral blood and tumor tissue collected before and during denosumab alone and in combination with anti-PD-1 treatment.