['melanoma', 'brain metastases']
['nivolumab', 'ipilimumab']

        Cohort 1 and 3

        Inclusion Criteria:

          1. ≥18 years of age.

          2. Written informed consent

          3. AJCC Stage IV (any T, any N, M1c) histologically confirmed melanoma or unknown primary
             melanoma. Patients must have at least 1 radiological definitive brain metastasis that
             is ≥ 5mm and ≤40mm measurable per RECIST version 1.1 guidelines.

          4. In patients with prior BRAF inhibitor treatment, intracranial disease progression must
             be demonstrated (RECIST >20% or new measurable brain metastases) compared with nadir
             of intracranial response during BRAF inhibitor treatment, and confirmed with a second
             MRI brain scan at any time from the beginning of the drug washout period (dabrafenib=5
             days, trametinib=14 days).

          5. No prior localised treatment for brain metastases (eg. surgery or radiotherapy).

          6. Neurologically asymptomatic from brain metastases.

          7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2, and life
             expectancy > 30 days.

          8. Able to undergo MRI with Gadolinium contrast agent.

          9. Adequate haematological, hepatic and renal organ function.

         10. Women of childbearing potential: negative serum pregnancy test and effective
             contraception from 14 days prior to study treatment until 23 weeks after the last
             dose.

         11. Men with female partner of childbearing potential to use effective contraception from
             14 days prior to study treatment until 31 weeks after the last dose.

             Exclusion Criteria:

         12. Any melanoma brain metastasis >40mm.

         13. Ocular melanoma.

         14. Prior treatment with an anti-PD-1 or anti-PD-L1 , anti-PD-L2, anti-CD137, or
             anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
             co-stimulation or checkpoint pathways.

         15. Patients with active, known or suspected autoimmune disease. Patients with 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 are permitted
             to enroll.

         16. Current systemic treatment with corticosteroids, except prednisone at
             nonimmunosuppressive doses of ≤ 10 mg/day (or equivalent). Past treatment for
             non-neurological symptoms allowed, if ceased 2 weeks prior to starting study
             treatment. Inhaled or intranasal corticosteroids (with minimal systemic absorption)
             may be continued if patient on a stable dose. Non-absorbed intraarticular steroid
             injections will be permitted.

         17. Any investigational drug or other systemic drug therapy for melanoma within 28 days or
             5 half-lives from baseline.

         18. Known to be HIV positive, or a positive test for hepatitis B and C .

         19. Another malignancy or concurrent malignancy unless disease-free for 3 years.

         20. Serious or unstable pre-existing medical conditions or other conditions that could
             interfere with the patient's safety, consent, or compliance.

         21. Pregnant or breastfeeding females.

         22. Administration of any form of live vaccination (such as influenza vaccine) within 30
             days of starting trial and anticipated use during the trial. Administration of any
             other vaccine is cautionary within 30 days of starting the trial and during the trial.

        Cohort 2 - per Cohorts 1 & 3, except patients must have at least one of the following:

          1. Failed prior local therapy for brain metastases (including surgery, stereotactic
             radiotherapy or whole brain radiotherapy) where disease has progressed per RECIST
             (>20% increase in SOD or new measurable brain metastases),

             and/or;

          2. Have current neurological symptoms related to brain metastases. IF they have received
             prior local therapy for brain metastases, the disease must have progressed per RECIST
             (>20% increase in SOD or new measurable brain metastases),

             and/or;

          3. Have leptomeningeal disease concurrently with measurable brain metastases. IF they
             have had failed prior local therapy for brain metastases, this must have progressed
             per RECIST (>20% increase in SOD or new measurable brain metastases).
      