SIL204 delivered up to 97% inhibition in KRAS Q61H pancreatic cancer cells and roughly 90% inhibition in colorectal models, with dose-dependent activity in lung cancer cell lines. In orthotopic pancreatic cancer models, the siRNA reduced primary tumor growth and metastatic spread. The candidate has shown activity across multiple KRAS variants, including G12D, G12V, G12R, Q61H, and G13D.
The core move: Silexion has selected AMS Advanced Medical Services as CRO to run its planned Phase 2/3 program of SIL204 in locally advanced pancreatic cancer, targeting a first-half 2026 start. The scope covers regulatory strategy, trial design, site start-up and management, and data analysis, with filings slated for Israel in Q4 2025 and the EU in Q1 2026. The protocol will test a dual-route administration strategy that combines intratumoral dosing to attack the primary tumor with systemic delivery to address micrometastatic disease. Silexion also points to an existing manufacturing tie with Catalent, signaling work on supply readiness as the program moves toward clinical execution.
Strategically, the CRO selection and cross-regional filing cadence indicate a bid for a seamless, potentially registration-enabling program outside the US, likely to compress timelines and cost. At the same time, regulators assess whether prior experience with a first-generation product can support skipping a traditional Phase 1. The dual-route design is essentially a delivery solution to the long-standing challenge of achieving therapeutic exposure in the fibrotic pancreatic tumor microenvironment while maintaining systemic coverage. Positioning SIL204 as mutation-agnostic could simplify screening in LAPC—dominated by G12D and G12V—compared with the narrow mutation gating associated with small-molecule KRAS inhibitors. The trade-off is operational complexity, which few oncology sites can execute at scale, and a higher bar for regulatory comfort with safety attribution when two administration modalities run in parallel.
For sites, this is an interventional study first and foremost. It requires interventional radiology capacity, image-guided injections, anesthesia resources, and close coordination between medical oncology, radiology, and pharmacy. The pharmacy will need siRNA handling protocols and cold-chain reliability, including repeat dosing logistics, if intratumoral administration is cyclical. The broader mutation coverage could widen eligibility and reduce the biomarker bottleneck; however, scheduling and procedural requirements will likely narrow the pool to high-acuity centers. For CROs and imaging vendors, expect central reads, procedural monitoring, and meticulous adverse event capture to demonstrate to regulators that local and systemic effects are clearly distinguished. Regulators will focus on standardization of the delivery device, lot-to-lot consistency of siRNA, and the justification for a pivotal-leaning design, given the absence of mature human safety data for this candidate. Catalent’s involvement should help with CMC and stability, but siRNA scale-up, sterility assurance, and release testing remain gatekeepers to activation.
What to watch next: protocol specifics around adaptive features, co-primary endpoints, and whether the study seeks conversion to resectability or focuses on survival in unresectable LAPC. Details on injection frequency, imaging schedules, and biopsy-based pharmacodynamic readouts will determine site burden and feasibility. Early regulator feedback in Israel and the EU will reveal whether a seamless Phase 2/3 is acceptable or if an initial safety lead-in is required. Competitive context is shifting, with variant-selective KRAS inhibitors moving up in pancreatic cancer; SIL204’s value hinges on demonstrating clinically meaningful tumor control across variants and a manageable procedure profile. Financing and manufacturing readiness will be practical constraints. The first signal to track is whether Silexion can successfully lock an experienced LAPC site network and publish a design that strikes a balance between ambition and operational realism.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
