SVV-001 With Nivolumab and Ipilimumab in Patients With Poorly Differentiated Neuroendocrine Carcinomas (NEC) or Well-Differentiated High-Grade Neuroendocrine Tumors (NET)

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 (see Inclusion #4), radiological confirmation of tumor is required.
• Parts 1B and 2 only: Measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 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 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.
• Adequate hematological, renal, and liver function defined as follows:

• a. Hepatic:

• i. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN) (≤5 × ULN if liver metastases are present)
• ii. Serum bilirubin ≤1.5 × ULN (unless due to Gilbert's syndrome or hemolysis)
• b. Renal:

• i. Creatinine clearance ≥50 mL/minute using Cockcroft Gault equation
• c. Hematologic:

• i. Absolute neutrophil count ≥1500 cells/µL
• ii. Platelet count ≥100,000 platelets/µL
• iii. Hemoglobin ≥9.0 g/dL
• iv. International normalization ratio (INR) within the institutional normal range
• v. 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:

• a. 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.
• b. 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 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.