Trial of Pembrolizumab and Radiotherapy in Melanoma

INCLUSION 1. Be willing and able to provide written informed consent for the trial 2. Have a diagnosis of stage III (unresectable) or stage IV cutaneous melanoma or melanoma of unknown primary, as per AJCC staging system 3. Informed metastatic disease by diagnostic biopsy 4. Be more than 18 years of age on day of signing informed consent 5. Have at least one lesion and a maximum of 3 which are appropriate targets for high dose radiotherapy. This lesion must be 1cm-5cm in size and measurable by RECIST v1.1 6. Have in addition at least one other lesion which will not be irradiated but must be measurable by RECIST v1.1 to assess the abscopal effect of the treatment 7. Have a performance status of 0 or 1 on the ECOG performance scale 8. Demonstrate adequate organ function as defined in table 1 below. All screening labs should be performed within 7 days of randomisation 9. Female patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to randomisation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required 10. Female patients of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year 11. Male patients should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy EXCLUSION 1. Has lesions that if irradiated would result in unacceptable radiation induced toxicity to normal tissue, in particular to the CNS and bowel 2. Requires palliative radiotherapy for symptom control 3. Is currently participating in or has participated in a study of an investigational agent or device within 4 weeks of the first dose of trial treatment 4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment 5. Has had a monoclonal antibody within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e. ≤Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier 6. Has had chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., ≤Grade 1 or at baseline) from adverse events due to a previously administered agent * Note: patients with an AE ≤Grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: if patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy 7. Has history of severe colitis related to previous immunotherapy treatment 8. Has a known additional malignancy that is progressing or requires active treatment Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy 9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis 10. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. 11. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 12. Has an active infection requiring systemic therapy 13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator 14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial 15. 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 16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 17. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) 18. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA \[qualitative\] is detected) 19. Has received a live vaccine within 30 days prior to the first dose of trial treatment