A phase 1 trial of the oncolytic virus SVV-001 with nivolumab and ipilimumab in patients with high-grade neuroendocrine neoplasms.

TPS2700 Background: Poorly differentiated neuroendocrine carcinomas (NECs), including small cell and large cell neuroendocrine tumors, and grade 3 neuroendocrine tumors (NETs) represent a highly aggressive disease collectively classified as high-grade neuroendocrine neoplasms (NENs). These tumors are marked by rapid tumor growth, early dissemination, genomic instability, and poor outcomes. Despite initial sensitivity to chemotherapy and radiotherapy, relapse rates remain high, and immune checkpoint inhibitors (ICIs) have demonstrated limited activity, highlighting a substantial unmet therapeutic need. Seneca Valley Virus (SVV-001) is a novel oncolytic picornavirus that has demonstrated synergistic antitumor activity with ICIs in preclinical models. Additionally, SVV-001 has shown a favorable safety profile and the ability to reverse ICI resistance in vivo, supporting its evaluation in combination with nivolumab + ipilimumab. Methods: This is an investigator-initiated, phase 1, dose-escalation and cohort-expansion study evaluating intratumoral SVV-001 in combination with nivolumab + ipilimumab in patients with histologically confirmed high-grade NENs who have progressed on at least one prior line of standard-of-care therapy. Eligible patients must have at least one lesion suitable to repeated intratumoral injections of SVV-001 (up to 6 injections every two weeks). The trial was activated in March 2025 at Sylvester Comprehensive Cancer Center, with enrollment currently ongoing and a planned accrual of up to 36 patients. Part 1 used a standard 3+3 dose-escalation design. Enrollment in the first three cohorts (Part 1A), evaluating single-dose SVV-001 in combination with nivolumab and ipilimumab, is complete with no dose-limiting toxicities observed. Enrollment into cohort 4 (Part 1B), which will evaluate multiple doses of SVV-001 (up to 6 injections) is planned to begin in February 2026 followed by Cohort 5. Part 2 consists of a cohort-expansion phase in which up to 6 additional patients will be treated at the optimal recommended phase 2 dose (RP2D) of SVV-001. The primary objective is to determine the maximum tolerated dose (MTD) and/or RP2D. Secondary objectives include radiographic progression-free survival (PFS), overall response rate (ORR), duration of response, clinical benefit rate (CBR), and safety. Correlative studies will assess viral kinetics, including viral release and viral load in plasma, as well as Tumor Endothelial Marker 8 (TEM8), a potential biomarker of SVV-001 sensitivity and its association with efficacy signals. Additional exploratory analyses will characterize the tumor immune microenvironment and gut microbiome markers in the dose-expansion cohort. ClinicalTrials.gov Identifier: NCT06889493. Clinical trial information: NCT06889493 .