Intratumoral Vusolimogene Oderparepvec in Combination with Pembrolizumab for the Treatment of Locally Advanced Unresectable or Metastatic Angiosarcoma

Inclusion Criteria

• Patients with biopsy proven cutaneous or non-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
• Have provided either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, obtained within 6 months prior to enrollment, with an associated pathology report, which must be submitted to the core laboratory for inclusion. Biopsy should be excisional, incisional or core needle. * Note: Fine needle aspiration is unacceptable for submission. A fresh biopsy is required at screening if an archival biopsy (within 6 months prior to enrollment) is not available
• Patients must have received and progressed following first-line standard of care, including a taxane or anthracycline based chemotherapy regimen
• Measurable disease based upon RECIST v 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 (β-human chorionic gonadotropin [hCG]) test at screening within 7 days of cycle 1 day 1
• Female patients 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 patients 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%)
• White blood cell count (WBC) ≥ 2.0 x 10^9/L
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
• Platelet count ≥ 100 x 10^9/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)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except patients with Gilbert syndrome who must have a total bilirubin of < 3.0 x ULN) or direct bilirubin ≤ ULN for a patient with total bilirubin level > 1.5 x ULN. If total bilirubin is > 1.5 x ULN but ≤ 3 x ULN, both aminotransferase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) levels must be ≤ 3 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN (or ≤ 5.0 x ULN, if liver metastases) Note: If aminotransferase levels (AST and/or ALT) are > 3 x ULN but ≤ 5 x ULN, total bilirubin must be ≤ 1.5 x ULN
• Alkaline phosphatase (ALP) ≤ 2.5 x ULN (or ≤ 5.0 x ULN, if liver or bone metastases)
• Blood creatinine ≤ 1.5 x ULN or measured or calculated (using Cockcroft) creatinine clearance ≥ 30 mL/minute for patients with creatinine levels > 1.5 x institutional ULN
• Prothrombin time (PT) or international normalization ratio (INR) ≤ 1.5 x ULN, and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN * Note: For patients who are on chronic anticoagulant therapy these patients 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
• Patients with a history of treated brain metastasis and, at the time of screening, asymptomatic central nervous system (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 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 cycle 1 day 1 (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

Exclusion Criteria

• Prior treatment with an oncolytic therapy
• Currently receiving antiviral drug therapy (e.g. valacyclovir or acyclovir)
• Has acute or chronic active hepatitis B and C virus infection or known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV) (defined as HCV ribonucleic acid [RNA] [qualitative]) or HIV infection * Note: No testing for hepatitis B, hepatitis C, or HIV is required unless mandated by local health authority or if clinically indicated
• Had systemic infection requiring IV antibiotics or other serious infection within 14 days prior to dosing
• Has active significant herpetic infections or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis)
• Systemic anticancer therapy within 4 weeks prior to enrollment or five half-lives, whichever is shorter, before the first administration of VO. Note: PD1/PD-L1 directed therapy is allowed
• Has not recovered from adverse events due to prior anti-cancer therapy to ≤ grade 1 or baseline. Note: Patients with toxicities after prior anticancer therapies that are not considered a likely safety risk such as grade ≤ 2 neuropathy or alopecia, or immune mediated adverse events (AEs) that are unlikely to recur with standard countermeasures (e.g., hormone replacement after adrenal crisis, stable endocrine insufficiencies such as thyroid and adrenal insufficiency), are an exception to this criterion and may qualify for the study in discussion with the principal investigator
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within four weeks prior to the first dose of study treatment. Note: Patients who have entered the follow-up phase of an investigational study may participate as long as it has been four weeks since the last dose of the previous investigational agent
• Has received prior radiotherapy within two weeks of start of study treatment. Note: Patients who are eligible must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease
• History of interstitial lung disease
• History of documented allergic reactions or acute hypersensitivity attributed to VO and pembrolizumab or any of its excipients
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacille Calmette-Guérin (BCG), and typhoid vaccine. Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed, however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. Available COVID-19 vaccines do not contain live virus and are allowed.
• Conditions requiring treatment with immunosuppressive doses (> 10 mg daily prednisone or equivalent) of systemic corticosteroids other than for corticosteroid replacement therapy within 14 days after enrollment
• Undergo major surgery ≤ 2 weeks prior to starting VO * Note: Patients who undergo major surgery requiring general anesthesia such as exploratory laparotomy or thoracotomy and are eligible for the study must adequately recover prior to starting study treatment. Procedures such as central line placement, endoscopies and tooth extractions under local anesthesia do not meet criteria for major surgery
• Has a history of (non-infectious) pneumonitis that required corticosteroids or has current pneumonitis
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs, or interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
• Has known psychiatric, alcohol abuse, or substance abuse disorders that would interfere with cooperating with the requirements of the study
• Has serious uncontrolled medical disorders such as uncontrolled hypertension, bleeding diatheses, uncontrolled diabetes
• Has clinically significant cardiovascular disease within 12 months from first dose of study drug, including New York Heart Association class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, history of myocarditis, or cardiac arrhythmia associated with hemodynamic instability
• Is a person deprived of their liberty by a judicial or administrative decision, or an adult person subject to a legal protection measure
• Has been treated with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to first dose and throughout the study
• Has an active, known, or suspected autoimmune disease. Note: Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Has a history of life-threatening toxicity related to prior immune therapy. Note: Toxicities that are unlikely to recur with standard countermeasures (e.g., hormone replacement after adrenal crisis) are allowed