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

1. Signed written informed consent and HIPAA authorization for release of personal health information.

2. Age ≥ 18 years at the time of consent.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

4. 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.

5. 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.

6. 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.

7. Must agree to undergo one on-treatment biopsy on week 4of the study; the biopsy at week 16 is optional.

8. 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.

9. Demonstrate adequate organ function, as listed below; all screening labs are to be obtained within 21 days prior to registration.

10. Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to study treatment. Note: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.

11. Females of childbearing potential must be willing to use an adequate methods of contraception, as outlined in the protocol. Oral contraception is required 14 days prior to initiation of study medications until 120 days after treatment discontinuation. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

12. Male patients with female partners must have had a prior vasectomy or agree to use an adequate method of contraception as outlined in the protocol- Contraception, starting with the first dose of study therapy through 150 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

13. As determined by the enrolling physician or protocol designee, willingness and ability of the subject to understand and comply with study procedures.

14. Previous radiation therapy is allowed, provided it is completed ≥14 days prior to starting denosumab and patient has recovered adequately from any related toxicities (grade≤1, or grade ≤2 that is stable for ≥3 months).

15. If patient has received adjuvant treatments, in particular ipilimumab and high dose interferon, any toxicities must have resolved to grade 1 or less. Grade 2 toxicities attributed to ipilimumab from autoimmune endocrinopathies that require permanent hormone replacement therapy are allowed as long as they are adequately treated. This implies that patients should be off systemic steroids for treatment of any of these or other autoimmune toxicities (e.g. colitis, rash). Subjects who have previously received PD-1 inhibitors in stage III (adjuvant) or stage IV are allowed as long as:

1. History of prior malignancy, with the exception of the following:

2. Has known active central nervous system (CNS) metastases that are symptomatic and require antiepileptic drugs or corticosteroids (any dose). Subjects with previously treated brain metastases may participate provided they are asymptomatic (i.e., no neurologic symptoms) for at least 2 weeks prior to the first dose of trial treatment and are not using steroids for at least 7 days prior to trial treatment. Patients with previously treated brain metastases should have evidence of stable brain metastases (without evidence of progression by imaging) for at least 2 weeks prior to the first dose of trial treatment. Patients with previously treated but grown brain metastases (or new brain metastases if there is no prior history of brain metastases) are still allowed in the study as long as the net growth of pre-existing brain lesions (or new brain lesions if there is no prior history of brain metastases) does not exceed 1-cm in largest diameter as measured by brain MRI with IV contrast (for example, a patient with pre-existing brain lesion(s) that has grown by 6-mm in the largest diameter and also has a new lesion that measures 4-mm in largest diameter can still be enrolled in the study; alternatively, a patient that has a new brain lesion that measures 1-cm in the largest diameter and no growth of pre-existing brain lesions can still be enrolled in the study). This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Subjects with leptomeningeal disease, detected either by brain MRI or by cytology (e.g. lumbar puncture) are also excluded.

3. Treatment with any investigational drug, immunotherapy or chemotherapy within 28 days prior to study treatment (i.e., initiation of denosumab). Treatment with any targeted therapy (e.g. Mitogen-Activated Protein Kinases (MAPK) inhibitors) is allowed as long as at least 15 days have elapsed since last dose of drug.

4. Patients discontinuing prior therapy with tyrosine kinase inhibitors for melanoma should be off these medications for at least 15 days before starting study treatment.

5. Prior PD-1/PD-L1 therapies in the adjuvant setting; targeted therapies or prior ipilimumab in the adjuvant setting are allowed.

6. Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk, if he/she were to participate in the study. This includes, but is not limited, to serious medical conditions or psychiatric illness likely to interfere with participation in this clinical study.

7. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy equivalent to daily doses of prednisone of 10 mg or greater (or an equivalent dose of other corticosteroids) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

8. Has a known history of active tuberculosis (Mycobacterium Bacillus Tuberculosis).

9. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

10. Hypersensitivity to nivolumab, pembrolizumab or denosumab or any of their excipients.

11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease-modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

12. Has a history of non-infectious pneumonitis that required systemic corticosteroids or evidence of interstitial lung disease or current active, non-infectious pneumonitis Episodic, brief (< 7 day) exposure to systemic corticosteroids (e.g. steroid taper for poison ivy or COPD exacerbation) is allowed.

13. Has a history of an acute coronary event (e.g. myocardial infarction) within 3 months since study entry, uncontrolled and symptomatic coronary artery disease, or congestive heart failure New York Heart Association class III/IV.

14. Has an active infection requiring systemic therapy within 7 days prior to treatment initiation.

15. Has a known history of Human Immunodeficiency Virus (HIV 1/2 antibodies).

16. Known serologic status reflecting active hepatitis B or C infection. Patients that are hepatitis B core antibody positive, but antigen negative, will need a negative polymerase chain reaction (PCR) prior to enrollment. [Note: Hepatitis B antigen or PCR positive patients will be excluded].

17. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.

18. Known active metabolic bone disease such as Paget's disease, Cushing's disease, hyperprolactinemia, over the last year 12 months, known history of osteoporosis that is symptomatic (e.g. history of fractures, bone pain), or hypercalcemia/hypocalcemia of any type (serum-free calcium being more than 1.1 x upper limit of normal (ULN) and less than 0.9 x, lower limits normal. LLN) over the last 2 weeks since study initiation that requires treatment beyond calcium and vitamin D supplementation.

19. Prior treatment with denosumab. Use of bisphosphonates for the treatment of metastatic bone disease, but not for hypercalcemia of malignancy, is allowed.

20. History of current evidence of osteonecrosis or osteomyelitis of the jaw. Note: The subject should be referred to dentist before study treatment initiation for poor dentition or other dental issues that, in the opinion of the treating physician, may increase the risk of osteonecrosis of the jaw.