A Phase 1b, Dose-escalation Study of Pexa-Vec (Thymidine Kinase-Deactivated Vaccinia Virus Plus GM-CSF) in Combination With REGN2810 (Anti-PD-1) in Patients With Metastatic or Unresectable Renal Cell Carcinoma (RCC)

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:

• Received treatment of approved anti PD-1 or anti-PD-L1 (dosed per label of the country providing the clinical site) for at least 12 weeks. History of anti-PD-L1 only is not allowed.

• Progressive disease after anti PD-1 or anti-PD-L1 will be defined according to RECIST 1.1. 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).

• 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 1.1 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.