IDOV-Safe: An intravenously deliverable oncolytic vaccinia virus for solid tumors refractory to standard of care—preliminary results from the pMMR/MSS CRC cohort.

e15556 Background: Metastatic pMMR/MSS colorectal cancer (CRC) remains challenging to treat following progression on oxaliplatin- and irinotecan- based therapies, with limited responsiveness to PD-1/PD-L1 inhibitors. Oncolytic viruses (OVs) offer a promising new approach to bio-immunotherapy for solid tumors. However, no effective OV therapy for MSS CRC has been reported to date. IDOV-Safe is a first-in-class, intravenously deliverable oncolytic vaccinia virus with potential against MSS CRC. Here, we present the first-in-human results from a phase I clinical trial evaluating the safety, PK, PD and preliminary efficacy of intravenous IDOV-Safe in the MSS CRC cohort, and also investigates potential combination strategies to enhance therapeutic outcomes. Methods: Only pMMR/MSS metastatic CRC patients who have failed from at least two lines of systematic therapy (including both oxaliplatin and irinotecan-based regimens) will be included in the study. In the dose-escalation phase, a “3+3” design was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose across four dose levels: 1×10 9 , 3×10 9 , 1×10 10 and 3×10 10 PFUs. For rapid dose titration, only one patient was enrolled at the first dose level. In the safety expansion phase, one or two dose levels will be selected, with 6-12 patients enrolled at each level. During this phase, patients who experience progression on IDOV-Safe monotherapy will transition to combination therapy with IDOV-Safe, Toripalimab (240 mg IV on day 1, every 3 weeks), and Fruquintinib (5 mg orally, day 1–14, every 3 weeks). The primary endpoints are the DLT rate and AEs of IDOV-Safe. Secondary endpoints include PK and PD characteristics, objective response rate, and progression free survival (PFS) in both the monotherapy phase (PFS1) and the combined therapy phase (PFS2). Results: Approximately 20 patients are expected to complete DLT evaluations by the end of February. DLTs will be assessed according to the protocol-defined criteria, such as grade 3 fever not resolved to ≤ grade1 within 24 hours et al. The recommended dose level for expansion phase will be determined during the Safety Monitoring Committee meeting, based on safety, PK, and efficacy data. Response will be evaluated according to RECIST1.1 criteria. PFS metrics are defined as follows: PFS1 is the duration from randomization to disease progression during IDOV-Safe monotherapy, and PFS2 is the duration from randomization to disease progression after the combination therapy with IDOV-Safe, Toripalimab, and Fruquintinib. Conclusions: Preliminary safety and efficacy data will be evaluated by February 28 th . Clinical trial information: NCT06380309 .