RP1 in Primary Melanoma to Reduce the Risk of Sentinel Lymph Node Metastasis

Inclusion Criteria: 1. Be willing and able to provide written informed consent for the trial. 2. Be ≥ 18 years of age on day of signing informed consent. 3. Have a diagnosis of pT3b, T4a or T4b melanoma on biopsy. Patients must have grossly visible residual tumor, or a positive deep or lateral margin on initial biopsy. Patients with uveal melanoma are not eligible. 4. Females of childbearing potential must have a negative beta-human chorionic gonadotropin (β-hCG) test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG during screening, before the first dose, and a negative urine pregnancy test on days of treatment (Day 1, 15 and 21). For serum and urine pregnancy tests and instructions (see Section 12.2). 5. Female patients of reproductive potential must agree to avoid becoming pregnant and adhere to a highly effective contraception method until 90 days after last dose of RP1 alone. For a definition of highly effective contraceptive methods and instructions of patients and partners (see Section 12.2). 6. Male patients of reproductive potential must agree to avoid impregnating a partner and adhere to a highly effective contraception method until 90 days after last dose of RP1 study agent and refrain from donating sperm during this period. For a definition of highly effective contraceptive methods and instructions of patients and partners (see Section 12.2). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. 8. Demonstrate adequate organ function. All screening labs should be performed within 30 days of treatment initiation. Baseline labs may be used as screening labs. Exclusion Criteria: 1. Prior treatment with an oncolytic virus therapy. 2. Has acute or chronic active hepatitis B and C virus infection or known history of hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or known active hepatitis C virus (HCV) (defined as HCV RNA \[qualitative\]) or HIV infection. Note: No testing for Hepatitis B, Hepatitis C, or HIV is required unless mandated by local health authority or clinically indicated. 3. Had systemic infection requiring IV antibiotics or other serious infection within 14 days prior to dosing. 4. Have active significant herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis). 5. Conditions requiring treatment with immunosuppressive doses (\> 10 mg daily prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement therapy within 14 days after enrollment. For the definition of replacement therapy (Section 11.0 Supportive Care and Management of Adverse Reactions/Events). 6. Major surgery ≤ 1 week prior to starting study drug. Note: Patients who undergo major surgery must adequately recover prior to starting study treatment. 7. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within four weeks prior to the first dose of study treatment. 8. History of documented allergic reactions or acute hypersensitivity reactions attributed to RP1 or any of its excipients. 9. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacille Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed, however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. Note: Available COVID-19 vaccines do not contain live virus. 10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs or interfere with the patient's participation for the full duration of the study or is not in the best interest of the patient to participate, in the opinion of the treating Investigator. 11. Has serious or uncontrolled medical disorders. 12. Has known psychiatric, alcohol abuse, or substance abuse disorders that would interfere with cooperating with the requirements of the study. 13. Is a person deprived of their liberty by a judicial or administrative decision, or an adult person subject to a legal protection measure. 14. Is a solid organ transplant recipient. 15. Has a concurrent malignancy requiring active systemic therapy or ongoing radiation. 16. Patients with tumors that are located near critical structures, such as the carotid artery or portal vein, or scalp lesions presenting with moderate to extensive bone erosion and tumors that may have invaded the heart, great vessels, or other critical structures will not be eligible because these area should not be injected. Injection through an ulcerated area of a lesion should be avoided.