Background: Uveal Melanoma (UM), although rare, is the most common intraocular malignant tumor in adults. Despite successful treatment of the primary tumor, approximately half of all patients will develop metastatic disease, mainly in the liver. Prognosis of metastatic UM is poor and overall survival (OS) has not improved over the last 30 years. Effective systemic therapies are lacking but recent literature suggests an improved effect of the combination of immunotherapy with ipilimumab/nivolumab (IPI/NIVO) as opposed to monotherapy. Percutaneous hepatic perfusion (PHP) is a liver-directed therapy that allows delivery of a high dose of melphalan to the liver with limited systemic toxicity. Efficacy of PHP has been demonstrated in phase II trials including patients with liver-dominant or liver-only metastases. In this study we combine PHP with IPI/NIVO with the goal of inducing a synergistic effect and improving disease control. The aim of the phase 1b is to establish the maximum tolerated dose (MTD) of IPI/NIVO when combined with PHP. The following randomized phase II trial aims to determine the efficacy of IPI/NIVO combined with PHP, compared to PHP alone. Methods: We initiated a prospective, single center, phase Ib and randomized phase II trial with a maximum of 88 patients in total. Patients with confirmed measurable hepatic UM metastases according to RECIST 1.1 and WHO performance score of 0-1 are included. Exclusion criteria are age > 75 years, treatment with systemic immunosuppressive medication and prior systemic treatment for metastasic UM. Phase Ib is a dose-escalation study consisting of two cohorts. The dose of IPI and NIVO is increased from 1mg/kg and 1mg/kg in cohort 1, to 1mg/kg and 3mg/kg, in cohort 2, respectively. The melphalan dose for the PHP is 3mg/kg (maximum dose of 220mg) in both cohorts. Treatment duration is 12 weeks consisting of 4 courses of IPI/NIVO with 2 PHP's in week 1 and 7. In phase II, the same treatment scheme as phase Ib is used in the treatment arm combining IPI/NIVO with PHP at the established MTD. The second treatment arm consists of 2 PHP's performed at a 6 week interval. Follow-up includes laboratory tests, CT-chest/abdomen and MRI-liver. Safety and toxicity are assessed according to the CTCAE V5.0. Radiological response is assessed according to RECIST 1.1 and irRECIST. Primary objective of phase Ib is to determine safety of the combination of IPI/NIVO with PHP defined by the MTD. In phase II the primary objective is the efficacy of combination treatment of IPI/NIVO with PHP defined by progression-free survival at one year. Secondary objectives include OS and overall response rate. Cohort 1 and 2 of phase Ib have been completed without dose limiting toxicities and the MTD is defined as IPI 1 mg/kg and NIVO 3 mg/kg. Accrual to phase II started in December 2020. An update will be presented at ASCO 2021. Clinical trial information: NCT04283890