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

For Pexa-Vec IV infusions (Part 1 / Part 2: Arm C and Arm D): Day -7, 1, 8, and 15), patients allocated to Part 1 or Part 2: Arm C or Arm D will receive an IV infusion of Pexa-Vec in approximately 250 mL buffered saline.

For Pexa-Vec IT Injections (Part 2 Arm A + Arm B), patients in Part 2, Arm A (and those in Arm B who progress on Cemiplimab monotherapy) will receive an IT injection of Pexa-Vec in a volume of buffered saline dependent on size of tumor(s).

For administration of Cemiplimab, Cemiplimab will be administered at a dose of 350 mg IV infusion over 30 minutes (±10 minutes) every 3 weeks per manufactures guidelines.

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 6 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 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).
• 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