Inclusion Criteria:

• Age ≥ 18 years.
• Measurable disease as defined below:
  • A non-nodal lesion is considered measurable if its longest diameter can be accurately measured as ≥ 2.0 cm with chest x-ray, or as ≥ 1.0 cm with CT scan, CT component of a PET/CT, or MRI;
  • A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in diameter as assessed using calipers (e.g., skin nodules) or imaging. In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended;
  • A malignant lymph node is considered measurable if its short axis is > 1.5 cm when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).
  • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease.
• Histologically or cytologically confirmed diagnosis of unresectable stage III or IV metastatic melanoma, meeting one of the following criteria:
  • Progressed after at least one line of FDA approved therapy (either immune checkpoint inhibitor [ICI] or targeted therapy);
  • Recurrent disease following initial surgical resection (may or may not have received adjuvant therapy);
  • Newly diagnosed or recurrent in-transit metastatic melanoma (may or may not be treatment naïve).
• The following laboratory values obtained ≤15 days prior to registration:
  • Hemoglobin ≥ 8.0 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 75,000/mm^3;
  • Total bilirubin ≤ 1.5 × ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3.0 × ULN;
  • Serum creatinine ≤ 2.0 × ULN;
  • Calculated creatinine clearance ≥ 40 ml/min using the Cockcroft-Gault formula below:
  • Cockcroft-Gault Equation: Creatinine clearance for males = (140 - age)(weight in kg) (72)(serum creatinine in mg/dL) Creatinine clearance for females = (140 - age)(weight in kg)(0.85) (72)(serum creatinine in mg/dL);
  • PT/INR/aPTT ≤1.5 × ULN OR if patient is receiving anticoagulant therapy INR or aPTT is within target range of therapy.
• ECOG Performance Status (PS) 0 or 1.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Persons able to become pregnant OR able to father a child must be willing to use an adequate method of contraception while on treatment and for 180 days (6 months) after last treatment dose on this study.
• Provide written informed consent.
• Patients enrolling in Rochester, MN, ONLY: Willingness to provide mandatory blood specimens for correlative research.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

Exclusion Criteria:

• Metastatic sites that drain lymphatic fluid into nodal beds which are not amenable to lymphatic infusion:
  • Sites of metastases limited only to the head and neck;
  • Sites of metastatic disease limited to the lungs and/or hilar lymph nodes.
• Metastatic uveal melanoma.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential who are unwilling to employ adequate contraception;
  • Persons expecting to conceive or father children during the study or within 180 days (6 months) after the last treatment on this study.
• Active CNS metastases not previously treated.
  • NOTE: patients with history of previously treated CNS metastases, not demonstrating evidence of progression for at least 12 weeks will be allowed.
  • NOTE: patients with leptomeningeal metastases are not eligible.
• Any of the following prior therapies:
  • Allogeneic hematopoietic stem cell transplantation (HSCT);
  • Solid organ transplantation.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immuno-compromised state, are eligible for this trial.
• Active autoimmune disease requiring systemic treatment < 2 years prior to registration; or documented history of severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents with use of disease modifying agents, corticosteroids, or immunosuppressive drugs.
  • NOTE: Exceptions are allowed for the following conditions:
  • Vitiligo;
  • Resolved childhood asthma/ atopy;
  • Intermittent use of bronchodilators or inhaled steroids;
  • Daily steroids at dose of ≤ 10mg of prednisone (or equivalent);
  • Local steroid injections;
  • Stable hypothyroidism on replacement therapy;
  • Stable diabetes mellitus on therapy (with or without insulin);
  • Sjögren’s syndrome;
  • Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) which is not considered a form of systemic treatment and is allowed.
• Uncontrolled intercurrent illness including, but not limited to:
  • Ongoing or active infection requiring systemic therapy;
  • Interstitial lung disease;
  • Serious, chronic gastrointestinal conditions associated with diarrhea (e.g., Crohn’s disease or others);
  • Known history of hepatitis B (i.e., known positive HBV surface antigen (HBsAg) reactive);
  • Known active hepatitis C (i.e., positive for HCV RNA detected by PCR);
  • Known active tuberculosis (TB);
  • Symptomatic congestive heart failure;
  • Unstable angina pectoris;
  • Unstable cardiac arrhythmia; or
  • Psychiatric illness/social situations that would limit compliance with study requirements (e.g., known substance abuse).
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• History of severe hypersensitivity reactions to other monoclonal antibodies or known hypersensitivity to the study intervention or its excipients, indocyanine green (ICG) dye or iodine.
• Prior history of Grade 4 immune related adverse event (irAE) with prior ICI therapy or failure to recover (< Grade 1) from immune-related adverse event(s) from prior ICI therapy.
• Any of the following therapies prior to registration:
  • Chemotherapy ≤ 28 days;
  • Immunotherapy ≤ 28 days;
  • Targeted therapies (e.g., dabrafenib) ≤ 21 days;
  • Other investigational agents ≤ 28 days;
  • Radiation therapy ≤ 14 days;
  • Minor surgical or interventional procedure ≤ 7 days;
  • Major surgical procedure ≤ 21 days.

Eligibility last updated 9/9/21. Questions regarding updates should be directed to the study team contact.