The purpose of this study is to measure the clinical benefits of the combination of RP2 and nivolumab as compared with the combination of nivolumab and ipilimumab in patients with metastatic uveal melanoma who have not been treated with immune checkpoint inhibitor therapy.

Key Inclusion Criteria:

• Patients who are 18 years of age or older at the time of signed informed consent.
• Patients with confirmed diagnosis of metastatic Uveal melanoma not amenable to surgical resection.
• Has at least 1 measurable and injectable tumor of ≥ 1 cm in longest diameter (≥ 1.5 cm in the shortest axis for a lymph node [LN]) that is amenable to serial RP2 injections.
• Must be willing to provide tumor biopsy samples.
• LDH ≤ 2 × upper limit of normal (ULN).
• Has adequate hematologic, hepatic and renal function
• Prothrombin time (PT) ≤ 1.5 × ULN (or international normalization ratio [INR] ≤ 1.3) and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• Life expectancy of > 6 months as estimated by the Investigator.

Key Exclusion Criteria:

• Any exposure to immune checkpoint inhibitor (ICIs) since the time of first being diagnosed with uveal melanoma.
• Known acute or chronic Hepatitis B or C infection or human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
• Current active significant herpetic infections or prior complications of HSV-1 infection.
• Any central nervous system (CNS) involvement of melanoma, including carcinomatous meningitis.
• Major surgery ≤ 2 weeks prior to the first dose of study intervention.
• Any bleeding, thrombotic and/or other event that places the patient at an unacceptable risk of complications of intratumoral therapy.
• Active, known, or suspected autoimmune disease requiring systemic treatment.
• Prior treatment with an oncolytic virus.
• Requires intermittent or chronic use of systemic (oral or IV) antivirals with known antiherpetic activity (eg, acyclovir).
• Systemic anticancer therapy or prior radiotherapy within 2 weeks of the first dose.
• Has received Investigation agent within 4 weeks or 5 half-lives (whichever longer) prior to the first dose.
• Conditions requiring treatment with immunosuppressive doses (> 10 mg per day of prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement therapy within 14 days after enrollment.

Additional inclusion/ exclusion criteria are outlined in the study protocol