This is a multi center, phase I pilot study of sequential ONCOS-102 and pembrolizumab in patients with advanced or unresectable melanoma progressing after PD1 blockade. The primary objective of the study is to determine the safety of sequential treatment with ONCOS-102 followed by pembrolizumab. The protocol aims to enroll patients into two cohorts: Part I: up to 12 patients will receive sequential treatment with ONCOS-102 followed by pembrolizumab. Part II: up to 12 patients will receive an initial treatment phase with ONCOS-102 followed by a treatment phase with ONCOS-102 in combination with pembrolizumab.

Inclusion Criteria:

• Adults 18 years of age or older.

• For US sites: Histopathologically confirmed melanoma with an injectable cutaneous or lymph node metastasis that has progressed in the opinion of the treating investigator despite administering a Food and Drug Administration (FDA) approved anti-PD1 agent, with or without ipilimumab.

• For European sites: Histopathologically confirmed melanoma with an injectable cutaneous or lymph node metastasis that has progressed in the opinion of the treating investigator despite administering a regulatory approved anti-PD1 agent, with or without ipilimumab.

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.

• Measurable disease according to RECIST 1.1.

• Acceptable coagulation status: international normalised ratio (INR) of blood clotting, prothrombin time and activated partial thromboplastin time within ≤1.5 x upper limit of normal (ULN).

• Completion of local therapy, such as radiation, surgical resection, injectable immunebased therapy, or topical pro-inflammatory agent, 21 days prior to first dose of protocol therapy.

• Adverse events from previous cancer therapies (excluding alopecia) must have recovered to grade 1 (CTCAE, most recent version). Stable grade 2 AEs such as endocrine conditions are allowed, and other chronic stable AEs may be considered on a case by case basis by the Principal Investigator.

• Clinical stability of brain metastases for at least 4 weeks prior to first day of study therapy.

• Acceptable liver and renal functions defined as:

  • Total bilirubin ≤1.5 x ULN (does not include patients with Gilbert's Disease)
  • Aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) ≤3.0 x ULN
  • Serum creatinine ≤1.5 x ULN

• Acceptable haematological function defined as (Patients can be transfused to meet the haemoglobin entry criteria):

  • Haemoglobin ≥9 g/dL
  • Neutrophils ≥1.5 x 10^9/L
  • Platelet count ≥75 x 10^9/L

• Able to provide valid written informed consent.

• All women of childbearing potential must have a negative urine or serum pregnancy test at screening.

• For US sites: All patients must agree to use barrier contraception (i.e. condom) during study treatment and for 2 months after the last virus treatment and 4 months after the last dose of chemotherapy and pembrolizumab.

• For European sites: All patients must agree to use highly effective contraception for at least 6 months (according to the latest country specific SmPC) after administration of CPO, up to 4 months after last dose of pembrolizumab, and up to 2 months after last dose of ONCOS-102, whichever comes last.

• For European sites: All women of child-bearing potential must agree to perform pregnancy testing throughout the study starting at baseline, every 3 weeks from day 22 until last dose of study medication (ONCOS-102 and pembrolizumab) and then every month for at least 6 months.

Exclusion Criteria:

• A concomitant medical condition requiring receipt of a therapeutic anticoagulant that in the opinion of the treating physician cannot safely allow for therapeutic injection of ONCOS-102 and tumor biopsies. Local clinical practice can be followed with regard to holding a therapeutic anticoagulant during invasive procedures such as biopsies.

• A concomitant medical condition that in the opinion of the treating physician would pose unreasonable additional risk to therapeutic injection of ONCOS-102.

• For US sites: Receipt of Investigational agents within 28 days prior to first dose of protocol therapy.

• For European sites: Current participation or participation in a study of an investigational agent within 28 days prior to first dose of protocol therapy. Note: participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

• Any symptomatic autoimmune disease (such as lupus, scleroderma, Crohn's disease, ulcerative colitis) that requires administration of >10mg of prednisone equivalent. Lower dose steroids for conditions such as hypophysitis are allowed.

• Any prior severe adverse event attributed to prior anti-PD1 therapy that, in the Principal investigator's opinion, would contraindicate pembrolizumab administration such as:

  • Grade 2 or higher pneumonitis
  • Grade 4 AST or ALT elevation
  • Grade 3 or higher colitis attributable to PD1 blockade; note that colitis attributable to ipilimumab is not excluded
  • Note: in the absence of clinical symptoms of pancreatitis, elevations of amylase or lipase are not contraindications to therapy on this trial

• Known active infection with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or HIV. Cleared HBV/HCV infection is not an exclusion, nor is HIV infection with cluster of differentiations 4 (CD4) counts >500 and an undetectable viral load.

• Active bacterial, viral, or fungal infections, requiring systemic therapy apart from anti-viral maintenance therapy for HIV.

• History of organ transplant.

• Patients requiring chronic systemic immunosuppressants, including steroids (prednisone daily equivalent of >10 mg).

• Brain metastases that are clinically unstable (e.g. showing unequivocal growth on imaging, requiring radiation therapy, or steroids >10mg of prednisone equivalent) within 4 weeks of first dose of study drug.

• Known severe congenital or acquired cellular or humoral immunodeficiency such as common variable immunodeficiency.

• For US sites: Women who are pregnant or breast-feeding currently or are planning to conceive during or up to 4 months after end of protocol therapy.

• For European sites: Women who are currently pregnant or breast-feeding or are planning to conceive during or up to 6 months after end of protocol therapy.