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 uvealmelanoma 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 Abtreatment, IL-2)

6. Local pre-treatment of uveal melanoma metastases is allowed (resection and/orthermal ablation), except for chemotherapy containing procedures (e.g.chemoembolization) and radio-embolization, and as long as patients have progressedwith measurable disease according to RECIST 1.1

7. No concurrent systemic immunosuppressive medications ≥ 10mg/day prednisone orequivalent. Topical, inhaled, nasal and ophthalmic steroids, and adrenal replacementtherapy 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 PTTin normal range, LDH < 2xULN

9. Women of child bearing potential (WOCBP) must agree to use a reliable form ofcontraceptive 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 orsquamous cell skin cancer, cervical cancer in situ or adequately treated othercancer with eradicative intent for which the patient has been continuouslydisease-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 autoimmunedisease, or history of syndrome that required systemic steroids or immunosuppressivemedications, 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 surfaceantigen or Hepatitis C ribonucleic acid (RNA)

6. History of congestive heart failure, active cardiac conditions, including unstablecoronary syndromes (unstable or severe angina, recent myocardial infarction),significant arrhythmias and severe valvular disease must be evaluated for risks ofundergoing general anesthesia.

7. History or evidence of clinically significant pulmonary disease e.g. severe COPDthat precludes the use of general anesthesia.

8. Underlying medical conditions that, in the Investigator's opinion, will make theadministration of study treatment hazardous or obscure the interpretation oftoxicity 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, orimmunosuppressive 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-coagulationtherapy.

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 systemicmalignancy

16. Pregnancy or nursing