A Clinical Trial Evaluating the Safety and Preliminary Effectiveness of HEPZATO with Immunotherapy in Patients with Metastatic Melanoma and Liver Metastasis

Inclusion Criteria

• Ability to understand and the willingness to sign a written informed consent document
• Histologically or cytologically confirmed metastatic melanoma with liver metastasis. Liver biopsy positive for presence of melanoma metastases is required
• Systemic treatment naïve in the unresectable/metastatic setting – prior adjuvant anti-programmed cell death-1 (anti-PD-1) and BRAF/MEK targeted therapy is allowed but must be > 6 months from the last treatment
• Evaluable/measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Individuals at least 18 years of age * Because no dosing or adverse event data are currently available on the use of HEPZATO KIT™ in combination with nivolumab and relatlimab in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Predicted life expectancy 3+ months
• Hemoglobin (Hgb) >= 10.0 g/dL (to be obtained within 28 days of registration) * NOTE: test/labs repeated on cycle 1 day 1 (C1D1) of therapy will not be used to determine eligibility * Must be repeated prior to the start of protocol therapy if > 28 days have elapsed from their most recent prior assessment * Laboratory tests need not be repeated if therapy starts within twenty-eight (28) days of their most recent prior assessment
• Platelets > 100,000/uL (to be obtained within 28 days of registration) * NOTE: test/labs repeated on cycle 1 day 1 (C1D1) of therapy will not be used to determine eligibility * Must be repeated prior to the start of protocol therapy if > 28 days have elapsed from their most recent prior assessment * Laboratory tests need not be repeated if therapy starts within twenty-eight (28) days of their most recent prior assessment
• Absolute neutrophil count (ANC) > 2,000/uL (to be obtained within 28 days of registration) * NOTE: test/labs repeated on cycle 1 day 1 (C1D1) of therapy will not be used to determine eligibility * Must be repeated prior to the start of protocol therapy if > 28 days have elapsed from their most recent prior assessment * Laboratory tests need not be repeated if therapy starts within twenty-eight (28) days of their most recent prior assessment
• Creatinine < 2.5 x institutional upper limit of normal (ULN) (to be obtained within 28 days of registration) * NOTE: test/labs repeated on cycle 1 day 1 (C1D1) of therapy will not be used to determine eligibility * Must be repeated prior to the start of protocol therapy if > 28 days have elapsed from their most recent prior assessment * Laboratory tests need not be repeated if therapy starts within twenty-eight (28) days of their most recent prior assessment
• Total bilirubin < 3 x ULN (to be obtained within 28 days of registration) * NOTE: test/labs repeated on cycle 1 day 1 (C1D1) of therapy will not be used to determine eligibility * Must be repeated prior to the start of protocol therapy if > 28 days have elapsed from their most recent prior assessment * Laboratory tests need not be repeated if therapy starts within twenty-eight (28) days of their most recent prior assessment
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 5 x ULN (to be obtained within 28 days of registration) * NOTE: test/labs repeated on cycle 1 day 1 (C1D1) of therapy will not be used to determine eligibility * Must be repeated prior to the start of protocol therapy if > 28 days have elapsed from their most recent prior assessment * Laboratory tests need not be repeated if therapy starts within twenty-eight (28) days of their most recent prior assessment
• Albumin >= 2.8 g/dL (to be obtained within 28 days of registration) * NOTE: test/labs repeated on cycle 1 day 1 (C1D1) of therapy will not be used to determine eligibility * Laboratory tests need not be repeated if therapy starts within twenty-eight (28) days of their most recent prior assessment
• International normalized ratio (INR) < 1.5 (to be obtained within 28 days of registration) * NOTE: test/labs repeated on cycle 1 day 1 (C1D1) of therapy will not be used to determine eligibility * Laboratory tests need not be repeated if therapy starts within twenty-eight (28) days of their most recent prior assessment
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. HIV testing not required
• For patients with a history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy. Hepatitis B testing not required
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Hepatitis C testing not required
• Patients with treated brain metastases are eligible if follow-up brain imaging at least 4 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification
• Individuals of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to study registration/randomization. If the test results are thought to reflect a false positive, per the investigator, alternative methods may be used to determine pregnancy status. A person of childbearing potential is anyone (regardless of sexual orientation, gender identity, having undergone a tubal ligation, or remaining celibate by choice) who was born with a uterus and at least one ovary and meets both of the following criteria: * Is post-menarcheal (i.e., has had at least one prior menses) * Has not undergone a hysterectomy or bilateral oophorectomy or has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• Individuals in sexual relationships that could result in pregnancy or impregnation of their partner must use an acceptable method of contraception (condoms, intrauterine device, etc.) from 14 days prior to planned C1D1 until 3 and 6 months after completing study treatment for males and females, respectively * Note: Includes, but is not limited to, barrier with additional spermicidal foam or jelly, intrauterine device, hormonal contraception (started at least 30 days prior to study enrollment), intercourse with individual who underwent vasectomy
• Willing to comply with all study procedures and be available for the duration of the study
• 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 eligibility. 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
• Patients must not have had radiotherapy (exception outlined below), 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
• 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)

Exclusion Criteria

• Diagnosis of metastatic uveal melanoma
• Prior treatment with HEPZATO KIT™ or nivolumab/relatlimab or nivolumab/ipilimumab
• Radiotherapy is permitted within 30 days prior to C1D1 as long as radiation is given with palliative intent and towards a non-target lesion
• History of hypersensitivity or treatment discontinuation due to grade 3+ immune-related adverse events (irAEs) from prior anti-PD-(L)1 therapy. Patients who are able to successfully resume immune checkpoint therapy without recurrence of grade 3 irAEs are eligible to participate
• Symptomatic or uncontrolled brain metastases, leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation
• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic corticosteroids (prednisone >= 10 mg/d or equivalent)
• Organ transplant recipients
• If a subject is pregnant or breastfeeding, they cannot take part in this study as the drugs used in this study may harm a fetus or breastfeeding baby
• 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
• Patients with Child-Pugh class B or C cirrhosis or with evidence of portal hypertension by history, endoscopy, or radiologic studies
• History or evidence of clinically significant pulmonary disease that precludes the use of general anesthesia
• Patients who are unable to be temporarily removed from chronic anti-coagulation therapy
• Patients with active bacterial infections with systemic manifestations (malaise, fever, leucocytosis) are not eligible until completion of appropriate antimicrobial therapy
• Patients with severe allergic reaction to iodine contrast, which cannot be controlled by premedication with antihistamines and steroids
• Patients with a history of or known hypersensitivity to melphalan or the components of the melphalan/hepatic delivery system (HDS) system
• Patients with a severe latex allergy leading to anaphylaxis
• Patients with a history of hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia
• 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)
• Patients with a history of gastrinoma * NOTE: For patients with a history of liver surgery, bile duct surgery, or major vasculature surgery, a CT angiogram or MR angiogram is required during screening to assure (after discussion with interventional radiology, surgery, or radiology) the patient does not have hepatic vasculature incompatible with perfusion, hepatofugal flow in the portal vein or known unresolved venous shunting
• Known varices at risk of bleeding, including medium or large esophageal or gastric varices, or active peptic ulcer
• Patients with an active infection, including hepatitis B and hepatitis C infection. Patients with anti-hepatitis B core antibody (HBc) positive or hepatitis B surface antigen (HBsAg) but deoxyribonucleic acid (DNA) negative are exception(s)
• Patients with prior Whipple’s procedure
• Uncontrolled endocrine disorders (per investigator discretion) including diabetes mellitus, hypothyroidism, or hyperthyroidism
• Not recovered from side effects of prior therapy to =< grade 1 (according to National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5). Certain side effects that are unlikely to resolve or develop into serious or life-threatening events (e.g. alopecia, endocrinopathies, lymphedema, etc.) are allowed at > grade 1
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements