Phase I dose escalation trial of STX-001, an LNP-encapsulated self-replicating mRNA expressing IL-12, in patients (pts) with advanced solid tumors.

9556 Background: STX-001 is a lipid nanoparticle-encapsulated self-replicating mRNA that activates innate immunity, promotes immunogenic cancer cell death, and expresses IL-12 to induce immune responses against tumors. Preclinical models demonstrated significant immune modulation and antitumor activity. Methods: Eligible pts had treatment-refractory advanced solid tumors with ≥ 1 clinically injectable lesions. Bayesian Optimal Interval design was used with an initial 3 + 3 run-in for dose escalation. STX-001 was administered intratumorally every 3 weeks. Dose-limiting toxicities (DLTs) were assessed during the first treatment cycle and response was evaluated by RECIST 1.1. Results: From May 29, 2024 to data cutoff (Dec 16, 2024), 14 pts were enrolled across four dose levels (30 - 900 µg). Common Gr ≥ 3 treatment-related adverse events, which included transient neutropenia (4 pts; 29%), lymphopenia (3 pts; 21%), ALT increase (2 pts; 14%), and AST increase (2 pts; 14%), were largely acute and self-limiting, and allowed ongoing dosing. There was no febrile neutropenia or drug-induced liver injury. One pt in the 900 µg cohort experienced DLTs (Gr 3 cytokine release syndrome and Gr 4 lymphopenia) but remained on study. IL-12 expression and robust IFN-γ induction were observed in the plasma. Tumor biopsies showed robust increases in PD-L1 and CD4/CD8 T cell staining post-treatment in both injected and non-injected lesions compared to baseline. 7 pts had undergone on-treatment disease assessment. 5 out of 7 pts had melanoma and were all refractory to PD-1 + CTLA-4 or LAG-3 inhibitors. 3 out of 5 melanoma pts had shrinkage of non-injected lesions (abscopal effects) including one with a confirmed RECIST complete response (CR; 100 µg cohort; prior treatments: PD-1 + LAG3, CTLA-4, and PD-1 inhibitors; metastases in skin and lymph nodes; subcutaneous lesion injected), one with a RECIST partial response (PR; 30 µg cohort; prior treatments: PD-1 + CTLA-4, PD-1, PD-1 + LAG3, and CTLA-4 inhibitors; metastases in skin, lung, and muscle; subcutaneous lesions injected), and one with 100% target lesion reduction with pronounced inflammatory response across multiple cutaneous/visceral lesions (30 µg cohort; prior treatments: PD-1 and CTLA-4 + PD-1 inhibitors; metastases in skin, lymph nodes, and lung; [sub]cutaneous lesions injected) and on-going clinical benefit (despite initial RECIST progression). ctDNA analysis, peripheral blood and tumor microenvironment profiling, PK, and other translational analyses are on-going. Conclusions: STX-001 demonstrates promising preliminary efficacy, robust immune activation, and a favorable safety profile. These results support the continued development of STX-001 both as monotherapy and in combination with immune checkpoint inhibitors. Dose optimization is ongoing. Clinical trial information: NCT06249048. Clinical trial information: NCT06249048