A Study of Recombinant Vaccinia Virus in Combination With Cemiplimab for Renal Cell Carcinoma

Inclusion Criteria: * Histologically or cytologically confirmed metastatic or unresectable clear cell renal cell carcinoma (ccRCC) * Part 2 Arm D ONLY: Patients must be refractory to anti PD-1 or anti-PD-L1 (either as monotherapy or in-combination with other approved checkpoint inhibitors or targeted therapies according to their approved label) and patients must meet all of the following criteria: 1. Received treatment of approved anti PD-1 or anti-PD-L1 (dosed per label of the country providing the clinical site) for at least 6 weeks. History of anti-PD-L1 only is not allowed. 2. Progressive disease after anti PD-1 or anti-PD-L1 will be defined according to RECIST v1.1. The initial evidence of progressive disease is to be confirmed by a second assessment, no less than 4 weeks from the date of the first documented progressive disease, in the absence of rapid clinical progression. (This determination is made by the Investigator; the Sponsor will collect imaging scans for retrospective analysis. Once progressive disease is confirmed, the initial date of progressive disease documentation will be considered the date of disease progression). 3. Documented disease progression within 12 weeks of the last dose of anti PD-1 or anti-PD-L1. Patients who were re-treated or on maintenance with anti-PD-1 or anti-PD-L1 will be allowed to enter the study as long as there is documented progressive disease within 12 weeks of the last treatment date. * Naive to systemic therapy for RCC or have progressed after, or were intolerant of, prior systemic therapy. * Measurable disease based on RECIST v1.1 criteria. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions * Karnofsky performance status of 70-100 * Age ≥20 years old (or appropriate age of consent for the region) * Adequate hematological, hepatic, and renal function Exclusion Criteria: * Known significant immunodeficiency due to underlying illness (e.g., human immunodeficiency virus \[HIV\] / acquired immune deficiency syndrome \[AIDS\]) and/or immune-suppressive medication including high-dose corticosteroids * Part 2 only: Arm A,B,C: Prior treatment with any anti-cancer immunotherapy, including therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (prior IL-2 or interferon allowed) . For Part 1: patients are excluded if they were intolerant to anti-PD-1 or anti-PD-L1 targeted therapies * Major surgery within 4 weeks of study treatment (minor surgical procedures are allowed) * Ongoing severe inflammatory skin condition requiring prior medical treatment * History of eczema requiring prior medical treatment * Tumor(s) invading a major vascular structure (e.g., carotid artery) or other key anatomical structure (e.g., pulmonary airway) OR viable central nervous system malignancy * Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural effusions. * Symptomatic cardiovascular disease, including but not limited to significant coronary artery disease (e.g., requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months. * Asymptomatic cardiovascular disease (current or past history) unless cardiology consultation and clearance has been obtained for study participation. * Inability to suspend treatment with anti-hypertensive medication for 48 hours prior to and 48 hours after all Pexa-Vec treatments * Use of interferon/pegylated interferon (PEG-IFN) or ribavirin that cannot be discontinued within 14 days prior to any Pexa-Vec dose * Known active Hepatitis B or Hepatitis C