First-in-human dose escalation trial of an engineered salmonella delivering L-methioninase in advanced bone and soft tissue sarcomas.

11530 Background: Advanced bone and soft-tissue sarcomas have limited treatment options. Tumor-selective methionine dependency is a known metabolic vulnerability. SGN1 is designed to deplete methionine locally within tumors via intratumoral colonization of an attenuated Salmonella vector expressing L-methioninase. Preclinical studies have demonstrated safety and targeted antitumor activity. Here, we report the results from the escalation and expansion phases of the Phase I study in patients (pts) with advanced bone and soft-tissue sarcomas. Methods: The Phase I study includes a dose-escalation phase where pts received intravenous (IV) (2.0×10⁸ to 4.0×10⁸ CFU) or intra-arterial (IA) infusion (2.0×10⁸ to 6.0×10⁸ CFU) once a week (QW) in 28-day cycles, followed by an expansion phase with the putative recommended Phase 2 dose (RP2D) (2.0×10⁸ CFU for IV or 6.0×10⁸ CFU for IA QW) in 6 cohorts, including pts with recurrent either bone or soft tissue sarcoma after at least 2 lines of chemo therapies. SGN1 was administered in combination with physician's choice systemic therapy. Administration of SGN1 was via one of three routes: IV, IA, or a combined IV/IA regimen. Efficacy was assessed by RECIST version 1.1. Results: At the cut-off of Aug 19, 2024, 25 pts with advanced bone and soft-tissue sarcomas were enrolled in the escalation and expansion phases (median follow-up of 5.6 months; range, 0.5-18.2), including pts with bone sarcoma (n=10) and soft tissue sarcoma (n=15). Treatment was administered via IV (n=13), IA (n=8), or a combined IV/IA (n=4) route. The disease control rate (DCR) was 76.0% (95% CI: 56.5, 93.0) in all, 70.0% (95% CI: 34.8, 93.3) in bone sarcoma, 80.0% (95% CI: 52.0, 95.6) in soft tissue sarcoma pts, and 69.2% (95% CI: 38.5, 90.9) in IV, 75.0% (95% CI: 34.8, 93.3) in IA, 100% in combined IV/IA route. Quantitative PCR analysis confirmed significant intra-tumoral colonization by SGN1 post-treatment. The median progression-free survival (mPFS) was 11.5 months (95% CI: 11.1, NE) in all, 11.1 months (95% CI: 1.1, NE) in bone sarcoma, not reached (NR) (95% CI: 3.2, NE) in soft tissue sarcoma pts, and NR (95% CI: 2.7, NE) in IV, 11.5 months (95% CI: 1.3, NE) in IA, NR (95% CI: 11.1, NE) in combined IV/IA route. Complete tumor necrosis was observed in at least two soft tissue sarcoma patients. In all pts, the most frequent treatment-related adverse events (TRAEs) were pyrexia (32.0%) and elevation of blood LDH increased (20.0%). No TRAEs leading to temporary drug discontinuation, no serious TRAEs resulting in withdrawal from the study, and no treatment-related deaths occurred. Conclusions: SGN1 exhibits a manageable safety profile, and showed encouraging clinical benefit in advanced bone and soft-tissue sarcoma, as evidenced by mPFS and DCR. The promising data from this phase I study supports further testing of SGN1 in Phase II studies. Clinical trial information: ChiCTR2400085361.