• Participants with biopsy proven cutaneous angiosarcoma that is locally advanced and unresectable or metastatic and has received and progressed on at least one prior immunotherapy based regimen within 6 months prior to screening.

• At least one measurable tumor of ≥ 1 cm in longest diameter or ≥ 1.5 cm in shortest diameter (for lymph nodes) and injectable lesions which in aggregate comprise \>= 1 cm in longest diameter.

• Participants must have received and progressed following first-line standard of care, including a taxane or anthracycline based chemotherapy regimen.

• Measurable disease based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

• Life expectancy of at least 3 months, in the opinion of the treating investigator.

• Females of childbearing potential must have a negative beta-human chorionic gonadotropin (beta-hCG) test at screening within 7 days of Cycle 1 Day 1.

• Female participants of reproductive potential must agree to avoid becoming pregnant and adhere to a highly effective contraception method until 90 days after last dose of VO alone or 120 days after last dose of VO and pembrolizumab.

• Male participants of reproductive potential must agree to avoid impregnating a partner and adhere to a highly effective contraception method until 90 days after last dose of VO study agent and refrain from donating sperm during this period.

• Age \<=18 years on the day of signed informed consent.

⁃ Eastern Cooperative Oncology Group (ECOG) performance status \<= 1 (Karnofsky ≥ 70%)

⁃ Adequate hematologic function including:

∙ White blood cell count (WBC) \>= 2.0 × 109/L

‣ Absolute neutrophil count (ANC) \>= 1.5 × 109/L

‣ Platelet count \>=100 × 109/L

‣ Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L (without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 2 weeks of dosing)

⁃ Adequate hepatic function including:

∙ Adequate renal function: Total bilirubin \<= 1.5 × upper limit of normal (ULN) (except participants with Gilbert Syndrome who must have a total bilirubin of \< 3.0 × ULN) or direct bilirubin \<=ULN for a participant with total bilirubin level \> 1.5 × ULN. If total bilirubin is \> 1.5 × ULN but \<= 3 × ULN, both aminotransferase (AST and ALT) levels must be \<= 3 × ULN.

‣ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<= 3.0 × ULN (or \<= 5.0 × ULN, if liver metastases) Note: If aminotransferase levels (AST and/or ALT) are \> 3 × ULN but \<= 5 × ULN, total bilirubin must be \<= 1.5 × ULN.

‣ Alkaline phosphatase (ALP) \<= 2.5 × ULN (or \<= 5.0 × ULN, if liver or bone metastases)

⁃ Blood creatinine \<= 1.5 × ULN or measured or calculated (using Cockcroft) creatinine clearance \>= 30 mL/minute for participants with creatinine levels \> 1.5 × institutional ULN.

⁃ Adequate coagulation: Prothrombin time (PT) or international normalization ratio (INR) \<=1.5 × ULN, and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) \<= 1.5 × ULN. Note: For participants who are on chronic anticoagulant therapy these participants may be enrolled if the pretreatment INR \< 2.5.

⁃ Adequate oxygen saturation: \>=92% on room air.

⁃ Ability to understand and the willingness to sign a written informed consent document.

⁃ Participants with a history of treated brain metastasis and, at the time of screening, asymptomatic CNS metastases are eligible, provided they meet all the following:

∙ Brain imaging at screening shows no evidence of interim progression for at least 4 weeks by repeat imaging, and clinically stable for at least 2 weeks

‣ Have measurable disease outside the central nervous system (CNS)

‣ Only supratentorial metastases allowed

‣ No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed

‣ No stereotactic or whole brain radiation within 14 days prior to C1D1.

⁃ Individuals with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.