Percutaneous Hepatic Perfusion in Patients With Hepatic-dominant Ocular Melanoma

The study will consist of 3 phases: a screening phase, treatment phase, and follow-up phase.

Screening Phase: Screening assessments will be conducted within 28 days prior to the
eligibility date to determine each patient's overall eligibility and baseline
characteristics. These assessments will include medical history, physical examination,
Eastern Cooperative Oncology Group (ECOG) performance status (PS), 12 lead electrocardiogram
(ECG), echocardiogram (ECHO), vital signs, full hematology and biochemistry, Quality of Life
questionnaire, radiologic assessments of baseline disease status and concomitant medications.

For patients with a history of liver surgery or major vasculature surgery, an angiogram
evaluation of their vasculature will be performed for compatibility for Percutaneous Hepatic
Perfusion (PHP) prior to confirming eligibility.

Eligibility date: This is the date on which all screening assessments have been completed and
the patient is determined to be eligible for the trial.

Treatment Phase: Eligible patients will be treated with Melphalan/HDS 3.0 mg/kg Ideal Body
Weight (IBW) and must begin treatment within 14 days being eligible. Melphalan/HDS treatment,
patients will receive up to 6 treatments. Each treatment cycle consists of 6 weeks with an
acceptable delay for another 2 weeks before the next planned treatment to allow for recovery
of melphalan-related toxicity, if needed. Tumor response will be assessed every 12 weeks (+ 2
weeks) until disease progression. If the patient receives only 1 treatment, the disease
assessment scans will be conducted 12 weeks after the date of the first treatment. The
assessment scans will be reviewed by an Independent Review Committee (IRC), also referred to
as Independent Central Review. At any time when progressive disease (PD) is observed, the
patient will be removed from further study treatment and followed until death. Melphalan/HDS
treatment will also be discontinued in the event that recovery from treatment related
toxicity requires more than 8 weeks from last treatment. An end-of-treatment visit will be
conducted approximately 6 to 8 weeks following the final study treatment. Ongoing treatment
related adverse events (AEs) at the end-of-treatment visit will be followed until the
severity is within one of the following parameters (1) Symptoms are resolved or return to
baseline; (2) CTCAE Grade < 1 or can be explained; (3) patient death. The maximum possible
duration of the study treatment for any patient will be 12 months.

NOTE: Active Melphalan/HDS patients (currently in treatment) on PHP-OCM-301 will continue
treatment on PHP-OCM-301A following the re-consenting process.

NOTE: Patients on PHP-OCM-301 that have completed treatment and are entering or are already
in the follow-up phase will be followed-up for survival and disease progression (as
applicable) on PHP-OCM-301A following the re-consenting process.

Follow-up Phase: Once the patient has completed the end-of-treatment (EOT) visit in
accordance with the schedule of events they will enter the follow-up phase. If the disease
has not progressed at the EOT (Section 6.2), the patient will need to continue with disease
assessment visits every 12 weeks (+ 2 weeks) until disease progression is documented. If the
disease has progressed before or at the EOT their follow-up is to be by phone every 3 months
for survival status until death.

Patients will be monitored, following the completion of study treatment, for the development
of myelodysplasia and secondary leukemia.

Inclusion Criteria:

1. Male or female patients ≥ 18 years of age.

2. Patients must weigh ≥ 35 kg (due to possible size limitations with respect to
percutaneous catheterization of the femoral artery and vein using the Delcath Hepatic
Delivery System).

3. 50% or less histologically or cytologically-proven ocular melanoma metastases in the
parenchyma of the liver.

4. Disease in the liver must be measurable by computed tomography (CT) and/or magnetic
resonance imaging (MRI).

5. Evidence of limited extrahepatic disease on preoperative radiological studies is
acceptable if the life threatening component of disease is in the liver. Limited
extrahepatic disease is defined in this protocol as follows: metastasis in bone,
subcutaneous, lung or lymph nodes that is amenable to resection or radiation and has a
defined treatment plan. Patients with extra-hepatic tumor burden which does not have a
defined treatment plan (i.e. monitor or is unable to be resected or radiated) must not
be included in the trial.

6. Scans used to determine eligibility (CT scan of the chest/abdomen/pelvis and MRI of
the liver) must be performed within 28 days prior to randomization. An MRI of the
liver is required at screening to validate that CT accurately reflects the extent of
disease in the liver. For patients with MRI intolerance, a 3-phase liver CT is to be
done in place of liver MRI.

7. Patients must not have chemotherapy, radiotherapy, chemoembolization,
radioembolization, or immunoembolization for their malignancy within 30 days prior to
treatment and must have recovered from all side effects of therapeutic and diagnostic
interventions except those listed in Appendix B of the study protocol.

8. Patients receiving anti programmed cell death protein 1 (PD-1) immunotherapy such as
pembrolizumab or nivolumab, or human cytotoxic T-lymphocyte antigen 4 blocking
antibody such as ipilimumab should wait 8 weeks before Melphalan/HDS treatment.

9. Patients must have an ECOG PS of 0-1 at screening and on the day prior to treatment.

10. Patients must have adequate hepatic function as evidenced by total serum bilirubin ≤
1.5 x the upper limit of normal (ULN) and a prothrombin time (PT) within 2 seconds of
the upper normal limit. Aspartate aminotransferase/alanine aminotransferase (AST/ALT)
must be ≤ 2.5 x ULN.

11. Patients must have a platelet count > 100,000/µL, hemoglobin ≥ 10.0 gm/dL, white blood
cell count (WBC) > 2,000/uL, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, and a
serum creatinine ≤ 1.5 mg/dL unless the measured creatinine clearance is > 40
mL/min/1.73 m2.

12. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
(β-human chorionic gonadotropin) within 7 days prior to randomization.

13. Provided signed informed consent.

Exclusion Criteria:

1. Patients with Child-Pugh Class B or C cirrhosis or with evidence of portal
hypertension by history, endoscopy, or radiologic studies.

2. Those with New York Heart Association functional classification II, III or IV active
cardiac conditions, including unstable coronary syndromes (unstable or severe angina,
recent myocardial infarction), worsening or new-onset congestive heart failure,
significant arrhythmias and severe valvular disease must be evaluated for risks of
undergoing general anesthesia.

3. History or evidence of clinically significant pulmonary disease that precludes the use
of general anesthesia.

4. Women of childbearing potential (WOCBP) i.e. fertile meaning not permanently
sterilized and having had a menstrual period within the past 12 months) unable to
undergo hormonal suppression to avoid menstruation during treatment.

5. WOCBP and fertile males (not permanently sterile by bilateral orchidectomy) unwilling
or unable to use highly effective contraception method for consent to at least 6
months after the last administration of study treatment (e.g. combined hormonal
contraception; progestogen-only hormonal contraception; Intrauterine device,
intrauterine hormone-releasing system; bilateral tubal occlusion, vasectomized partner
or sexual abstinence).

6. Females that are pregnant or breastfeeding patients

7. Patients taking immunosuppressive drugs; however, oral corticosteroids ≤ 10 mg/day are
allowed.

8. Patients who are unable to be temporarily removed from chronic anti-coagulation
therapy.

9. Patients with active bacterial infections with systemic manifestations (malaise,
fever, leucocytosis) are not eligible until completion of appropriate therapy.

10. Patients with severe allergic reaction to iodine contrast, which cannot be controlled
by premedication with antihistamines and steroids (because a hepatic angiogram is
needed for the Delcath system procedure).

11. Patients with a history of or known hypersensitivity to melphalan or the components of
the Melphalan/HDS system.

12. Patients with latex allergy.

13. Patients with a history of hypersensitivity to heparin or the presence of
heparin-induced thrombocytopenia.

14. Patients with a history of bleeding disorders or evidence of intracranial
abnormalities which would put them at risk for bleeding with anti-coagulation (e.g.,
strokes, active metastases).

15. Patients with a history of gastrinoma, hepatic vasculature incompatible with
perfusion, hepatofugal flow in the portal vein or known unresolved venous shunting.

16. Known varices at risk of bleeding, including medium or large esophageal or gastric
varices, or active peptic ulcer.

17. Patients with prior Whipple's procedure.

18. Patients with brain metastases or presence of other intracranial lesions at risk for
bleeding by history or baseline radiologic imaging.

19. Patients with active liver infection, including Hepatitis B and Hepatitis C infection.
Patients with anti-hepatitis B core antibody (HBc) positive, or hepatitis B surface
antigen (HBsAg) but DNA negative are exception(s).

20. Uncontrolled endocrine disorders including diabetes mellitus, hypothyroidism, or
hyperthyroidism.

21. Received any investigational agent for any indication within 30 days prior to first
treatment.

22. Not recovered from side effects of prior therapy to ≤ Grade 1 (according to National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v. 4.03).
Certain side effects that are unlikely to develop into serious or life-threatening
events (e.g. alopecia) are allowed at > Grade 1.

23. Cancers other than ocular melanoma for which the patient is currently under treatment
or still deemed not to be cancer free.