Evaluation of Denosumab in Combination With Immune Checkpoint Inhibitors in Patients With Unresectable or Metastatic Melanoma

Inclusion Criteria: 1. Histologically confirmed unresectable or metastatic melanoma as per AJCC 7 staging system. 2. Age ≥ 18 years 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 4. Patient willing and able to provide written informed consent. 5. Treatment naïve (no prior systemic therapy for unresectable or metastatic melanoma). Note that prior adjuvant or neoadjuvant melanoma therapy (except anti-PD1 and/or anti-CTLA-4 therapy) is permitted if it was completed at least 6 weeks prior to allocation, and all related adverse events have either returned to baseline or resolved. 6. Willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study. 7. Measurable disease by CT or MRI per RECIST 1.1 criteria. 8. Patients with asymptomatic brain metastasis may be considered for enrollment. These patients can have up to 3 lesions that are ≤ 1.5 cm in diameter. The brain metastasis may be naïve to local therapy or have previously received local therapy (surgery, stereotactic radiotherapy/radiosurgery but not whole brain radiotherapy) and are stable. Asymptomatic from brain metastases at study entry implies that these patients are without corticosteroid, antiepileptics, analgesia or any other treatment for the management of neurological symptoms. Patients with completely resolved neurological symptoms are permitted. 9. At least 2 weeks since the completion of prior therapy, including surgery or radiotherapy. 10. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to registration * WBC ≥ 2000/μL * Neutrophils ≥ 1500/μL * Platelets ≥ 100 x103/μL * Haemoglobin \> 9.0 g/dL * Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below): Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL * AST/ALT ≤ 3 x ULN * Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) * Serum calcium of albumin-adjusted calcium ≥ 2.0 mmol/L 11. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Appropriate methods of contraception includes: * Intrauterine device with a documented failure rate of less than 1% per year. * Vasectomised partner who is sterile prior to the female partner patient's commencement of study treatment and is the sole sexual partner for that female. * Double barrier contraception: male condom and occlusive cap (diaphragm or cervical /vault caps). 12. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of treatment. 13. Men who are sexually active with a WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with a WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men, do not require contraception. Effective contraception includes: * Documented vasectomy and sterility * In the partner - intrauterine device with a documented failure rate of less than 1% per year * Double barrier contraception: male condom and occlusive cap (diaphragm or cervical/vault caps). 14. Patients must agree to have archival tumour material collected. This can either be from a resected lymph node, primary melanoma, or metastatic site. Where possible, the most recently acquired tumour specimen should be provided. If archival tumour tissue is not available, subjects must consent to allow the acquisition of additional tumour tissue prior to trial entry. 15. Patients enrolled on the biopsy cohort must be agreeable to have serial tumour biopsies during the study. Exclusion Criteria: 1. Patients are excluded if they have symptomatic, large volume brain metastases and/or any evidence of leptomeningeal disease. Large volume brain metastasis for this study is defined as more than 3 brain metastasis and/or any of the brain metastasis being greater than 1.5 cm in dimension. Note: patients with larger brain metastasis (up to 3 cm) that has been adequately treated with prior surgery or stereotactic radiation are permitted to be enrolled as long as they have adequately recovered from the local therapy. 2. Neurological symptoms from brain metastases present at baseline (resolved neurological symptoms, prior to enrolment, are permitted). 3. Patients with uveal melanoma are excluded. 4. Prior exposure to a CTLA-4 inhibitor (e.g. ipilimumab, tremelimumab), PD-1 inhibitor (e.g. nivolumab, pembrolizumab), PD-L1 inhibitor (e.g. MEDI-4736), PD-L2 inhibitor, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. 5. Prior systemic treatment with a BRAF and/or MEK inhibitor 6. Prior treatment with denosumab. 7. Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast. 8. Life expectancy of ≤ 6 months. 9. Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw. 10. Active dental or jaw condition, which requires major oral surgery. Patients who have undergone a tooth extraction in less than 4 weeks should be reviewed carefully to ensure they have healed well. 11. Surgery or radiotherapy within less than 2 weeks of Cycle 1 Day 1. Any clinically relevant sequelae from the surgery or radiotherapy must have improved to grade 1 prior to Cycle 1 Day 1. 12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 13. Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enrol if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger 14. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \>10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 15. Any investigational drug or other systemic drug therapy for melanoma within 28 days or 5 half-lives from baseline. 16. Pregnant or breastfeeding females. 17. Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. 18. Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 19. Allergies and Adverse Drug Reaction 1. History of allergy to study drug components. 2. History of severe hypersensitivity reaction to any monoclonal antibody. 20. Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable. 21. For those being registered to Arm B (ipilimumab + nivolumab + denosumab), the use of any vaccines against infectious diseases (e.g. influenza, varicella etc.) within 6 weeks of initiation of study therapy.