An Oncolytic Virus (SVV-001) in Combination with Nivolumab and Ipilimumab for the Treatment of Neuroendocrine Cancers or High-Grade Neuroendocrine Tumors

Inclusion Criteria

• Male or female patients, 18 years of age or older at the time of consent.
• Life expectancy of 6 months or greater as assessed by the treating oncologist.
• Have advanced metastatic disease that has progressed on at least one line of available therapy.
• Histologically or cytologically confirmed diagnosis of grade 3 well-differentiated neuroendocrine tumor (NET) or poorly differentiated neuroendocrine carcinoma (NEC; large-cell neuroendocrine carcinoma, small-cell carcinoma, mixed neuroendocrine non neuroendocrine carcinoma). Note: if an archival tissue sample collected ≤ 2 years from enrollment is unavailable at screening for diagnostic confirmation, at the principal investigator’s (PI’s) discretion, a screening biopsy will be ordered.
• For patients in part 1A, in addition to histological or cytological confirmation of NEC or NET, radiological confirmation of tumor is required.
• Parts 1B and 2 only: Measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 or immune-related Response Evaluation Criteria in Solid Tumors (iRECIST). At least one lesion must be suitable for multiple injections (up to 6 injections every 2 weeks) with SVV-001. Lesions for injection must be ≥ 10 mm and ≤ 50 mm in longest diameter and deemed safe and suitable for injection by the investigator.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Recovered to grade 1 or baseline from any clinically significant toxicity associated with prior treatments (excluding alopecia) prior to initiation of investigational medicinal product (IMP) administration.
• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN) (≤ 5 × ULN if liver metastases are present).
• Serum bilirubin ≤ 1.5 × ULN (unless due to Gilbert’s syndrome or hemolysis).
• Creatinine clearance ≥ 50 mL/minute using Cockcroft Gault equation.
• Absolute neutrophil count ≥ 1500 cells/µL.
• Platelet count ≥ 100,000 platelets/µL.
• Hemoglobin ≥ 9.0 g/dL.
• International normalization ratio (INR) within the institutional normal range.
• Normal prothrombin time (PT) and partial thromboplastin time (PTT).
• For part 2 expansion cohort patients only, patients will submit archival tissue at screening and undergo a post-treatment biopsy according to the treating institution’s guidelines with the following exceptions: * If an archival tissue sample collected ≤ 2 years from enrollment is unavailable at screening, at the PI’s discretion, a screening biopsy will be ordered. * Participants will not undergo a biopsy procedure for collection of the post-treatment biopsy if, in the discretion of their treating physician, the participant’s condition has deteriorated to the point where performance of a biopsy procedure would place the participant at an increased risk for complications beyond what is reasonably expected for a biopsy collected as part of the participant’s standard medical care.
• Women of childbearing potential must agree to use a reliable form of contraceptive during the trial treatment period and for at least 7 months following the last dose of IMP.
• Male patients must agree to use an adequate method of contraception during the trial treatment period and for at least 7 months following the last dose of IMP.
• Patient is willing and able to comply with all protocol-required assessments, visits, and procedures.
• Provide written informed consent prior to performing any trial-related procedure.

Exclusion Criteria

• Any active second malignancy within the 2 years prior to the screening visit, unless the patient has undergone curative surgery for the tumors such as in situ cervical cancer or squamous cell cancer of the skin.
• Has had cytotoxic chemotherapy or radiation therapy within 3 weeks; and less than 5 half-lives or 6 weeks, whichever is shorter, from prior biologic therapies, prior to the first dose of SVV-001.
• Has undergone a major surgical procedure (as defined by the investigator) or significant traumatic injury within 28 days prior to the first dose of SVV-001.
• Has any physical abnormality of the tissue/organ to be biopsied that would put the patient at increased risk of bleeding secondary to the injection and/or biopsy.
• Has received a live-virus immunization within 30 days prior to the screening visit or anticipates receiving a live virus immunization during the trial or within 30 days of the last treatment with IMP.
• Presence of an active autoimmune or inflammatory disease requiring systemic treatment within the past 2 months or a documented history of clinically severe autoimmune disease that requires systemic steroids or other immunosuppressive medications. Local steroid injections, intermittent use of topical, inhaled, ophthalmologic, intra-articular, or intranasal corticosteroids, or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent would not result in exclusion from the trial.
• Presence of primary immunodeficiency or receiving systemic steroids of > 10 mg/day prednisone or equivalent or other immunosuppressive agents within 14 days prior to the first dose of SVV-001.
• Any active infection, including known infection with human immunodeficiency virus (HIV), active hepatitis, or seropositive for hepatis B immunoglobulin (Ig) M core antibody or hepatitis C ribonucleic acid (RNA) at the screening visit.
• Patients with a history of solid-organ or bone marrow transplant.
• Known hypersensitivity to ipilimumab or nivolumab or their excipients.
• Has known untreated central nervous system metastases. Patients with treated brain metastases are eligible as long as they are stable and there is no evidence of progression for at least 4 weeks after central nervous system-directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the screening period.
• Any clinically significant (i.e., active) cardiovascular disease, including cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication.
• Patients with an ejection fraction (EF) < 50 on a two-dimensional (2D) echocardiogram (ECHO).
• Patients whose baseline pulse oximetry (saturation of peripheral oxygen [SpO2]) is < 92% on room air.
• Any chronic illness, psychiatric condition, or social situation that is life threatening or, in the opinion of the investigator, renders the patient unsuitable for participation in a clinical trial due to possible noncompliance or would place the patient at an unacceptable risk and/or have the potential to affect interpretation of the results of the trial.
• Female participants who are breastfeeding and/or who have a positive pregnancy test result prior to receiving any treatment with IMP.
• Patients with impaired decision-making capacity.