A first-in-human, intra-tumoral AAV2- RUNX3 gene therapy (RX001) for advanced KRAS-mutant NSCLC (NCT06934590): Phase 1 trial in progress

Background: RUNX3 is a key tumor suppressor frequently silenced in KRAS-mutant non-small cell lung cancer (NSCLC), where its loss contributes to aberrant differentiation and tumor progression. In preclinical models, restoration of RUNX3 expression regressed the oncogenic KRAS-driven NSCLC cells. RX001 is a recombinant AAV2 vector encoding RUNX3 (rAAV2-RUNX3) designed for direct intra-tumoral (IT) administration to restore RUNX3 expression within the tumor microenvironment and inhibit tumor growth. This first-in-human Phase 1 study evaluates the safety, feasibility, and biological activity following IT administration of RX001. Methods: This is open-label, multicenter, dose-escalation Phase 1 trial (NCT06934590) conducted at four sites in the Republic of Korea. Eligible patients are adults with unresectable or metastatic KRAS-mutant NSCLC who have progressed after standard systemic therapies and who have at least one lesion suitable for IT injection. RX001 is administered as a single IT dose on Day 1 across three dose levels using a standard 3+3 design. Safety monitoring includes assessment of dose-limiting toxicities, evaluation of acute and delayed AAV-related toxicities, and determination of the recommended Phase 2 dose. Endpoints : The primary endpoint is the incidence of treatment-related serious adverse events (SAEs). Key secondary endpoints include objective response rate (ORR) and change in target tumor size. Eligibility: Key inclusion criteria include histologically confirmed KRAS-mutant NSCLC, prior receipt of appropriate standard therapies, ECOG performance status 0-1, and adequate organ function. Exclusion criteria include prior receipt of intra-tumoral therapy and uncontrolled autoimmune or immune-mediated conditions. Correlative Studies: Correlative analyses will evaluate immune responses following AAV administration, including anti-AAV antibodies, CD4/CD8 T-cell activation, and IFN-gamma levels in peripheral blood. Viral shedding will also be monitored in multiple clinical specimens. Trial Status: The trial is open as of September 2025, with enrollment ongoing across all sites.