Intralesional Influenza Vaccine for the Treatment of Stage I-IV Melanoma

Inclusion Criteria:

• Males or females

• 18 to 99 years of age

• Histologically confirmed cutaneous melanoma by historical pathology report review,clinical Stage I-III (Cohort #1), or Stage IV (Cohort #2) cutaneous melanoma

• At least one, biopsy-proven, palpable melanoma tumor deposit suitable forintralesional injection measuring ≥ 1 cm by digital caliper (with digitalphotography documentation) or ultrasound (with ultrasound image documentation)

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

• Absolute neutrophil count (ANC) >= 1.5 x 10^3/mm^3 (drawn at or not more than 30days prior to the screening visit)

• Hemoglobin (Hgb) >= 9 g/dL (drawn at or not more than 30 days prior to the screeningvisit)

• Platelet count >= 100 x 10^3/mm^3 (drawn at or not more than 30 days prior to thescreening visit)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limitof normal (ULN) or =< 5 x ULN in patients with liver metastases (Cohort 2 only) (drawn at or not more than 30 days prior to the screening visit)

• Prothrombin time =< 1.5 x ULN (drawn at or not more than 30 days prior to thescreening visit)

• Total bilirubin =< 1.5 x ULN (unconjugated bilirubin of < 3 x ULN for patients withknown Gilbert syndrome) (drawn at or not more than 30 days prior to the screeningvisit)

• Creatinine clearance of >= 50 ml/min by Cockcroft-Gault equation (drawn at or notmore than 30 days prior to the screening visit)

• Women of childbearing potential (WOCBP) must agree to use effective contraceptivemethods from screening until at least:

• Cohort 1: 14 days after the surgical resection for subjects in Cohort 1

• Cohort 2:

• Nivolumab: 5 months after the last dose of either nivolumab orintralesional Flucelvax, whichever is later

• Pembrolizumab: 4 months after the last dose of either pembrolizumab orintralesional Flucelvax, whichever is later

• Ipilimumab: 3 months after the last dose of either ipilimumab orintralesional Flucelvax, whichever is later

• Relatlimab + nivolumab (marketed under the trade name Opdualag): 5 monthsafter the last dose of either Opdualag or intralesional Flucelvax,whichever is later.

• Combination ipilimumab with other checkpoint inhibitor: Whichever islater:

• 3 months after the last dose of either ipilimumab or intralesionalFlucelvax

• Above-bulleted recommendation for nivolumab or pembrolizumab

• Non-childbearing potential is defined as a woman who meets either of the followingcriteria: a) postmenopausal state defined as no menses for 12 months without analternative medical cause, or b) documented hysterectomy, bilateral tubal ligation,or bilateral oophorectomy

• Effective contraception methods are defined as one of the following:

• True abstinence, defined as refraining from heterosexual intercourse, when thisis in line with the preferred and usual lifestyle of the subject

• Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulationmethods), declaration of abstinence for the duration of a trial, and withdrawalare not acceptable methods of contraception

• Condoms and spermicide

• Diaphragm and spermicide

• Oral or implanted hormonal contraceptive

• An intra-uterine device

• WOCBP must have a negative pregnancy test (serum or urine)

Exclusion Criteria:

• Known allergy or intolerance to influenza vaccination

• Subjects with condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone/equivalent) or other immunosuppressive medications within 14days of study drug administration

• Active, known or suspected autoimmune disease

• Active brain metastasis or leptomeningeal metastasis

• Diagnostic biopsy of ocular or mucosal melanoma

• Any melanoma therapy within 6 months of enrollment; though prior surgical resectionis permitted

• Incarcerated patients

• Patients known to be HIV positive are eligible if they meet the following criteriawithin 30 days prior to randomization: stable and adequate CD4 counts (≥ 350 mm^3),and serum HIV viral load of < 25,000 IU/ml. Patients may be on or off anti-viraltherapy so long as they meet the CD4 count criteria

• Pregnant or lactating patients

• Patients incapable of independently providing consent