The purpose of this project is to test the addition of a new treatment called denosumab to
standard immunotherapies for patients with metastatic melanoma. Denosumab has been used for
many years to help treat cancers such as prostate cancer and breast cancer, but it is not
currently used in melanoma. We hope the addition of denosumab to current melanoma therapies
will make these treatments work better without adding to the side effects.
Who is it for? You may be eligible to join this study if you are aged 18 years or over and
have been diagnosed with metastatic melanoma (melanoma that has spread).
Study details: Nivolumab and ipilimumab are approved treatments for advanced melanoma in
Australia and overseas. Patients with metastatic melanoma, who are not enrolled in a study,
are commonly prescribed nivolumab alone or the combination of nivolumab and ipilimumab as
standard care. However, there is limited information on the effectiveness and safety of these
treatments in combination with denosumab. Recent melanoma research in animal models has shown
that denosumab can make immunotherapies such as ipilimumab and nivolumab work better. Because
denosumab has been used in patients with breast and prostate cancer for a long time and is
safe, we now want to test the benefits and safety of adding denosumab to immunotherapies in
1. Histologically confirmed unresectable or metastatic melanoma as per American Joint
Committee on Cancer (AJCC) staging system
2. Equal or greater than 18 years of age
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
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. At least 2 weeks since the completion of prior therapy, including surgery or
9. Screening laboratory values must meet the following criteria and should be obtained
within 14 days prior to randomisation/registration
10. 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.
11. 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.
12. Men who are sexually active with 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 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.
13. 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.
14. Patient enrolled on the biopsy cohort must be agreeable to have serial tumour biopsies
during the study.
1. Patients are excluded if they have ever had any brain or leptomeningeal metastases.
2. 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 or any other antibody or drug specifically targeting T-cell costimulation or
immune checkpoint pathways.
3. Prior systemic treatment with a BRAF and/or MEK inhibitor.
4. Prior treatment with denosumab.
5. 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.
6. Life expectancy of less than or equal to 6 months.
7. Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw.
8. Active dental or jaw condition, which requires oral surgery, including tooth
9. Non-healed dental/oral surgery.
10. 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.
11. 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
12. 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
13. 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.
14. Any investigational drug or other systemic drug therapy for melanoma within 28 days or
5 half-lives from baseline.
15. Pregnant or breastfeeding females.
16. 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.
17. Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
18. Allergies and Adverse Drug Reaction
1. History of allergy to study drug components.
2. History of severe hypersensitivity reaction to any monoclonal antibody.
19. Patients with symptomatic or impending cord compression unless appropriately treated
beforehand and clinically stable.
20. Use of any vaccines against infectious diseases (e.g., influenza, varicella, etc.)
within 3 weeks (21 days)of initiation of study therapy.