LUMINOS-102: Lerapolturev With or Without Immune Checkpoint Blockade in Advanced PD-1 Refractory Melanoma

Inclusion Criteria: 1. ≥ 18 years of age 2. Prior CDC-recommended vaccination series against PV, and has received a boost immunization with trivalent IPOL® (Sanofi-Pasteur SA) at least 1 week, but less than 6 weeks, prior to Day 1 a. NOTE: Patients who are unsure of their vaccination status must provide evidence of anti-PV immunity prior to enrollment, as applicable 3. Has biopsy proven unresectable cutaneous melanoma and is willing to undergo tumor biopsy prior to the first dose of study drugs and at prespecified intervals during the study 1. Patients with ocular, acral or mucosal melanoma are not eligible 2. Patients with M1c or M1d disease are NOT eligble. 3. Submission of an archival biopsy sample is allowed in lieu of the baseline tumor biopsy, provided the tissue is ≤4 months old and the participant received no intervening systemic/intratumoral anti-cancer therapy since the biopsy was acquired. 4. Must have at least 1 lesion that is amenable to biopsy. The lesion must be safely accessible as determined by the investigator and should not be located at sites that require significant risk procedures to biopsy. Examples of sites considered to be of significant risk include but are not limited to the following: the brain, lung, mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel wall. 4. Has ≥ 2 melanoma lesions that are accurately measurable by caliper or a radiological method according to RECIST 1.1 criteria 1. One lesion must be injectable- defined as a visible or palpable cutaneous, subcutaneous, or nodal melanoma lesion ≥10 mm in longest diameter or multiple injectable melanoma lesions which in aggregate have a longest diameter of ≥10 mm and where the minimum lesion size is ≥5 mm 2. Note that visceral lesions (eg, liver, lung, retroperitoneal, subpleural lesions) are not considered injectable for the purposes of this trial. 5. Has had confirmed progression of disease (PD) while receiving at least 6 weeks (\> 1 dose) of an FDA-approved anti-PD-1/L1 therapy (as monotherapy or in combination) for the treatment of melanoma. Note the following details: 1. Initial PD as defined by RECIST v1.1 2. Confirmation of PD per iRECIST must occur by repeat assessment ≥ 4 weeks from initial evidence of PD, in the absence of rapid clinical progression. 3. Those who discontinue anti-PD-1/L1 therapy after at least 6 weeks (\> 1 dose) and have confirmed PD per iRECIST within 12 weeks of their last anti-PD-1/L1 dose are also eligible, provided the anti-PD-1/L1 was not stopped due to toxicity requiring permanent discontinuation 4. Those treated with anti-PD-1/L1 in the adjuvant setting and who have biopsy-confirmed progression either while receiving anti-PD-1/L1-based therapy or ≤ 12 weeks after their last dose of anti-PD-1/L1 therapy are allowed NOTE: Adjuvant is defined as therapy received after surgical resection of disease such that the patient has no evidence of disease when the anti-PD-1/L1 therapy is initiated. Patients with known BRAF mutation must have also failed or refused to receive BRAF-targeted therapy (alone or in combination with MEK inhibitor) to be eligible. 6. Eastern Cooperative Oncology Group (ECOG) status of 0-1 7. Serum lactate dehydrogenase (LDH) levels ≤ 3 x upper limit of normal (ULN) 8. Adequate bone marrow, liver and renal function as assessed by the following: 1. Hemoglobin ≥ 9.0 g/dl, patients may be transfused 2. Lymphocyte count ≥ 0.5 x 10\^9/L (500 µL) 3. Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (1500 µL) 4. Platelet count ≥ 100 x 10\^9/L (100,000 µL) without transfusion 5. AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN), with the following exceptions: Patients with documented liver metastases: AST and ALT ≤ 5 x ULN; Patients with documented liver or bone metastases: ALP ≤ 5 x ULN 6. Serum bilirubin ≤ 1.5 x ULN with the following exception: Patients with known Gilbert disease: serum bilirubin level ≤ 3 x ULN 7. Measured or calculated (per institutional standards) creatinine clearance ≥ 30 ml/min (GRF can also be used in place of creatinine clearance) 8. For patients not receiving therapeutic anticoagulation: INR, PT, PTT (or aPTT) ≤ 1.5 x ULN 9. Life expectancy of \>12 weeks 10. Signed informed consent form (ICF) indicating that participant understands the purpose of, and procedures required for the study, and is willing/able to participate in the study Exclusion Criteria: 1. Has biopsy-proven ocular, acral or mucosal melanoma 2. Has M1c or M1d disease 3. No more than one prior systemic anti-cancer regimen (monotherapy or combination) for management of melanoma. Additional details noted below: 1. Adjuvant anti-cancer therapy administered ≥ 6 months prior to the first injection of lerapolturev does NOT count as a line of treatment. 2. Patients with BRAF mutant melanoma may enroll if they have received ≤ 2 prior lines of systemic anti-cancer therapy only if one of those lines of therapy was a BRAF-targeted regimen (alone or in combination with MEK inhibitor). 3. A line of therapy is defined as a regimen in which at least 2 doses of systemic anti-cancer therapy (monotherapy or combination) was administered, and the regimen was discontinued because of progressive disease 4. Uncontrolled tumor-related pain. Participants requiring pain medication must be on a stable regimen at study entry. 1. Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period 2. Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment 5. Grade ≥2 pleural effusion, pericardial effusion, or ascites 6. Active or history of autoimmune disease or immune deficiency within previous 2 years, with the following exceptions: 1. History of autoimmune-related endocrinopathy (e.g. adrenal insufficiency, hypothyroidism, Type 1 diabetes mellitus, etc.) that is managed by hormone replacement therapy (e.g. hydrocortisone, thyroid hormone, insulin, etc.) 2. Eczema, psoriasis, or lichen simplex chronicus with dermatologic manifestations only (eg, patients with psoriatic arthritis are excluded), provided all of the following conditions are met: i. Rash must cover \<10% of body surface area ii. Disease is well-controlled at baseline and requires only low-potency topical corticosteroids iii. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within 12 months of Day 1 7. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan a. History of radiation pneumonitis in the radiation field (fibrosis) is allowed. 8. History of a positive HIV RNA test (HIV 1 or 2 RNA by PCR) 9. Known active hepatitis B virus (HBV) infection (chronic or acute) a. NOTE: Participants with a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test are allowed. 10. Known active hepatitis C virus (HCV) infection a. NOTE: History of a positive HCV antibody test, but negative HCV RNA test is allowed. 11. Active tuberculosis 12. Significant cardiovascular disease, such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months of Day 1, unstable arrhythmia, or unstable angina 13. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks or 5 elimination half-lives- whichever is shorter, prior to treatment, or has not recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy are eligible 1. Note: Anti-PD-1/L1 within 4 weeks prior to Day 1 is allowed 2. If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. 14. History of other malignancy within 2 years prior to Day 1, with the exception of those with a negligible risk of metastasis or death (e.g., resected cutaneous basal cell carcinoma, or other cancers with 5-year OS of \>90%) 15. Severe infection within 4 weeks prior to Day 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia a. Prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are allowed. 16. Prior allogeneic stem cell or solid organ transplantation 17. Treatment with a live, attenuated vaccine within 4 weeks prior to Day 1 18. Treatment with systemic immunosuppressive medication within 4 weeks prior to Day 1, with the following exceptions: 1. Participants who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 2. Patients receiving mineralocorticoids (e.g., fludrocortisone), or systemic prednisone equivalent corticosteroid doses of \<10mg per day are eligible for the study 19. Known hypersensitivity to pembrolizumab, nivolumab, or any of the respective excipients 20. Requires therapeutic anticoagulation and cannot discontinue anticoagulation safely during the day prior, day of, and day after each lerapolturev injection a. NOTE: Participants receiving anticoagulation with warfarin at the time of study entry are allowed if they can be transitioned to an alternative anticoagulant (eg, low molecular weight heparin or direct oral anticoagulants) prior to the first dose of lerapolturev. Anyone transitioned from warfarin to an oral anticoagulant prior to the first dose of lerapolturev should have an INR \<1.5x upper limit of normal in order to participate. Antiplatelet agents (eg, aspirin, clopidogrel, etc.) are not considered anticoagulants for the purposes of this study (ie, are allowed) 21. A pregnant or nursing female, or women of child-bearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception starting from signed ICF through 150 days after last anti-PD-1 dose 22. History of human serum albumin allergy 23. History of neurological complications due to polio virus infection 24. History of agammaglobulinemia 25. Concurrent participation in a separate interventional clinical trial during this study. 26. Any underlying medical condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromises the participant's well-being) or that could prevent, limit, or confound protocol-specified assessments