(P 433) PHASE I DOSE ESCALATION TRIAL OF STX-001, AN LNP SELF-REPLICATING MRNA EXPRESSING IL-12, IN PATIENTS WITH REFRACTORY TUMORS INCLUDING SARCOMAS

Objective: STX-001 is a lipid nanoparticle-encapsulated self-replicating mRNA that activates innate immunity, promotes immunogenic cell death, and expresses IL-12. Preclinical models had significant immune modulation and antitumor activity.

Methods: Open-label phase 1 trial using Bayesian Optimal Interval design with 3 + 3 run-in dose escalation. Eligible patients (pts) had advanced solid tumors with ≥ 1 injectable lesion. STX-001 was administered intratumorally once every 3 weeks. Response was evaluated by RECIST 1.1. Cutoff dates were April 3, 2025 (safety/demographics), and May 1, 2025 (efficacy).

Results: 22 pts were enrolled across 5 doses (10 - 900 ug): 1 angiosarcoma, 16 melanoma, 5 others. Post-treatment biopsy of angiosarcoma pt (300 ug) with prior chemotherapy, tyrosine kinase inhibitor, and surgery showed complete pathological response with high CD4/CD8 and PD-L1 expression. 13 melanoma pts were efficacy evaluable; all refractory to anti-PD-1. Notable results are 1 RECIST complete response (100 ug; skin/lymph node metastases (mets); subcutaneous lesion injected), 2 RECIST partial response (30 ug; skin/lung/muscle mets; subcutaneous lesions injected, and 900 ug, lymph node mets, nodal lesion injected), and 1 with 100% target lesion reduction and inflammatory response across cutaneous/visceral lesions after initial progression (30 ug; skin/lymph node/lung mets; [sub]cutaneous lesions injected). Biopsies demonstrated robust increases in PD-L1 and CD4/CD8 in injected/non-injected lesions. Plasma IL-12 and IFN-γ were observed. Grade ≥ 3 treatment-related adverse events included transient neutropenia (4 pts; 18%), lymphopenia (3 pts; 14%), ALT increase (2 pts; 9.1%), and AST increase (2 pts; 9.1%). No drug-induced liver injury reported. One DLT (Grade 3 CRS and Grade 4 lymphopenia) in the 900 ug cohort; pt remained on study.

Conclusion: STX-001 shows preliminary efficacy, immune activation, and tolerability in refractory tumors, including sarcomas, supporting the continued development of STX-001 as monotherapy and in combination with immune checkpoint inhibitors. Dose optimization is ongoing. Clinical trial information: NCT06249048