A phase I trial of intratumoral STX-001: A novel self-replicating mRNA expressing IL-12 alone or with pembrolizumab in advanced solid tumors

Abstract

Background: STX-001 is a multi-mechanistic lipid nanoparticle encapsulated synthetic self-replicating mRNA, engineered to express the IL-12 cytokine for an extended duration when administered intratumorally. A murine surrogate of STX-001 induces deep durable responses in multiple preclinical solid tumor models. This Phase 1 open-label, multi-center first-in-human dose-escalation trial evaluates the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of STX-001 alone, or in combination with pembrolizumab in patients with treatment refractory advanced cancers. Methods: Approximately 30 adults ≥18 years of age with histologically confirmed advanced solid tumors that are refractory to standard treatments will be enrolled. The study will consist of two arms, an STX-001 monotherapy arm and an STX-001 + pembrolizumab combination arm, enrolling approximately 15 patients each. Key eligibility criteria include ECOG status 0 or 1, a tumor lesion amendable to injection, and confirmed prior disease progression. STX-001 will be administered every 3 weeks (q3w) for 3 doses and then every 6 weeks (q6w) for a further 3 doses. Tumor biopsies will be obtained at baseline and after the first STX-001 administration. Primary endpoints will include safety and maximum tolerated dose (MTD), with secondary endpoints encompassing pharmacokinetics and preliminary efficacy as measured by RECIST 1.1. To determine the MTD, this study will employ the Bayesian optimal interval (BOIN) design, with the 3 + 3 design run-in and a recommended phase 2 dose (RP2D) will be determined. Tumor response will be assessed using RECIST 1.1 criteria. Exploratory pharmacodynamic analyses will assess tumor-infiltrating lymphocytes and STX-001 mRNA in baseline and on-treatment biopsies, evaluate inflammatory cytokine profiles in plasma, determine immune activation in circulating immune cells, and measure circulating tumor DNA (ctDNA) for molecular response assessment.