PHP and Immunotherapy in Metastasized UM

Inclusion Criteria:

1. Age between 18-75 yrs
2. World Health Organization (WHO) Performance Status 0 or I
3. 50% or less histologically or cytologically confirmed unresectable metastatic uveal melanoma in the parenchyma of the liver
4. Hepatic metastases, confined to or predominantly in the liver
5. No prior systemic treatment (including chemotherapy, vaccine therapy, monoclonal Ab treatment, IL-2)
6. Local pre-treatment of uveal melanoma metastases is allowed (resection and/or thermal ablation), except for chemotherapy containing procedures (e.g. chemoembolization) and radio-embolization, and as long as patients have progressed with measurable disease according to RECIST 1.1
7. No concurrent systemic immunosuppressive medications ≥ 10mg/day prednisone or equivalent. Topical, inhaled, nasal and ophthalmic steroids, and adrenal replacement therapy are allowed.
8. Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 6.5 mmol/L, Creatinine ≤ 2x ULN, AST ≤ 2.5 x ULN, ALT ≤ 2.5 x ULN, Total bilirubin ≤ 1.5 X ULN, INR and PTT in normal range, LDH \< 2xULN
9. Women of child bearing potential (WOCBP) must agree to use a reliable form of contraceptive as described in paragraph 5.4.
10. Men must agree to the use of male contraception as described in paragraph 5.4.
11. Absence of additional severe and/or uncontrolled concurrent disease
12. No prior, or ongoing other malignancy, except adequately treated basal cell or squamous cell skin cancer, cervical cancer in situ or adequately treated other cancer with eradicative intent for which the patient has been continuously disease-free for \> 2 years.
13. No aberrant vascular anatomy of the liver that precludes PHP

Exclusion Criteria:

1. Cerebral or meningeal metastasized uveal melanoma
2. Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy;
3. Prior immunotherapy (tumor vaccine, cytokine, or growth factor)
4. Known history of infection with Human Immunodeficiency Virus;
5. Active infection requiring therapy, positive serology for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA)
6. History of congestive heart failure, active cardiac conditions, including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), significant arrhythmias and severe valvular disease must be evaluated for risks of undergoing general anesthesia.
7. History or evidence of clinically significant pulmonary disease e.g. severe COPD that precludes the use of general anesthesia.
8. Underlying medical conditions that, in the Investigator's opinion, will make the administration of study treatment hazardous or obscure the interpretation of toxicity determination or adverse events;
9. Latex allergy, and known hypersensitivity/allergy to ipilimumab, nivolumab, melphalan or heparin
10. Prior Whipple's Surgery
11. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
12. History of or current immunodeficiency disease, splenectomy or splenic irradiation; prior allogeneic stem cell transplantation;
13. Patients who are unable to be temporarily removed from chronic anti-coagulation therapy.
14. Patients with active bacterial infections with systemic manifestations (malaise, fever, leucocytosis) are not eligible until completion of appropriate therapy.
15. Use of other investigational drugs before study drug administration for systemic malignancy
16. Pregnancy or nursing