Neo IRENIE (NEOadjuvant Ipilimumab, RElatlimab, NIvolumab Evaluation)

This clinical trial is for patients with cutaneous melanoma which has spread to the lymph nodes (known as stage 3 melanoma) and for patients with any stage of mucosal melanoma. The study is for those patients who have disease that can be surgically removed. The standard treatment for these patients is surgery to remove the affected tumour, lymph nodes, and any other deposits of melanoma, followed by drug therapy (known as adjuvant therapy). The most common drug therapy used to treat melanoma after surgery is known as 'immunotherapy'. Immunotherapy works by boosting the body's own immune system to better recognise and kill cancer cells. The aim of the study is to offer new immunotherapy combinations to 3 cohorts of patients who are known to be poor responders to standard immunotherapy regimens. Three cohorts of patients will be included: 1. Patients with resectable stage 3 cutaneous melanoma who have a predictive biomarker test result that indicates: Cohort 1a - they will be poor responders to standard anti-PD-1 immunotherapy (n=168) Cohort 1b - they will be high responders to standard anti-PD-1 immunotherapy (n=\~154) 2. Patients with resectable stage 3 cutaneous melanoma who have had a recurrence of melanoma despite having standard anti-PD-1 based immunotherapy (n=111). 3. Patients with resectable mucosal melanoma, at any stage of disease. Mucosal melanoma is known to respond poorly to stabdard immunotherapy (n=60). This research will test 6 combinations of immunotherapy which are given before surgery. Treatment given before surgery is known as 'neoadjuvant' treatment. Neoadjuvant treatment is standard for many cancers, including melanoma. The purpose of neoadjuvant immunotherapy is to increase the body's natural immune response by training it to recognise the evasive cancer cells before they are removed at surgery, and to shrink or destroy the melanoma, which may make surgery easier. This has been shown to reduce the chance of melanoma recurring after surgery. The drugs used in this study are called 'nivolumab', 'relatlimab', and 'ipilimumab' and 'pembrolizumab' In this trial, there are 5 different study treatment combinations. Each combination uses different mechanisms to potentially overcome the predicted resistance to standard immunotherapy. There are 4 phases to the study: 1. Neoadjuvant treatment with one of the new immunotherapy combinations 2. Surgery 3. Adjuvant treatment with standard immunotherapy, IF the neoadjuvant therapy has not been effective enough to clear more than 10% of cancer cells. 4. Follow up for recurrence and survival to the end of 10 years The main goal is to learn which of the new immunotherapy combinations are most effective at destroying the melanoma cells before surgery for each cohort of patients. The other important goals are to learn which treatment is best at preventing the return of melanoma over 10 years and which increases survival from melanoma. The investigators also want to evaluate the side effects patients may have to treatment and how this affects the quality of life. The investigators will also continue to research biomarkers in blood, tumour tissue and stools to identify possible mechanisms for better response to therapy. The study will be conducted in Australia and a total of 493 patients will be involved.