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

Inclusion Criteria

• ≥ 18 years of age
• 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

• 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
• Patients with ocular, acral or mucosal melanoma are not eligible
• Patients with M1c or M1d disease are NOT eligble.
• 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.
• 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.
• Has ≥ 2 melanoma lesions that are accurately measurable by caliper or a radiological method according to RECIST 1.1 criteria
• 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
• Note that visceral lesions (eg, liver, lung, retroperitoneal, subpleural lesions) are not considered injectable for the purposes of this trial.
• 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:
• Initial PD as defined by RECIST v1.1
• Confirmation of PD per iRECIST must occur by repeat assessment ≥ 4 weeks from initial evidence of PD, in the absence of rapid clinical progression.
• 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
• 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.
• Eastern Cooperative Oncology Group (ECOG) status of 0-1
• Serum lactate dehydrogenase (LDH) levels ≤ 3 x upper limit of normal (ULN)
• Adequate bone marrow, liver and renal function as assessed by the following:
• Hemoglobin ≥ 9.0 g/dl, patients may be transfused
• Lymphocyte count ≥ 0.5 x 10^9/L (500 µL)
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500 µL)
• Platelet count ≥ 100 x 10^9/L (100,000 µL) without transfusion
• 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
• Serum bilirubin ≤ 1.5 x ULN with the following exception: Patients with known Gilbert disease: serum bilirubin level ≤ 3 x ULN
• Measured or calcul