Early clinical activity and tumor transcriptional modulation of AU409, a first-in-class transcription regulator, in advanced solid tumors and hepatocellular carcinoma: Results from two phase I studies

Background: AU409 is a first-in-class small molecule that modulates transcription at TATA-box regulatory elements. Two parallel phase I studies in the US and Asia are evaluating AU409 as monotherapy in solid tumors and hepatocellular carcinoma (HCC). We report interim clinical outcomes and exploratory biomarker data. Methods: In the U.S. study (NCT05791448), patients (pts) received escalating doses between 60 and 420 mg orally once daily. In the Asia study (NCT06374485), pts received 120, 210, and 300 mg. Eligible pts had advanced solid tumors with liver dominant disease in the US while the Asia study was limited to HCC. Other criteria included child pugh A status and preserved organ function. The primary endpoint is to determine the maximum tolerated dose and safety. Secondary endpoints include objective response rate and PK. Pre- and on-treatment biopsies were obtained in the U.S. study for exploratory RNA seq analysis. Results: Eighteen patients have been recruited (U.S. n=10; Asia n=8). The most common tumor type is HCC (n=7 in US and 8 in Asia). Median age was 65 and 51.5 in the US and Asia respectively. All HCC pts received prior immunotherapy with a median of 1 (1-3) and 1 (1-2) prior lines of therapy respectively. No dose-limiting toxicities have been noted. MTD has not been reached, and accrual continues at 420 mg in the US and 300mg in Asia. Treatment related adverse events (TRAEs) occurring in more than 1 patient in the US were nausea, vomiting, diarrhea (5 each), ALT and AST elevation (4), and anorexia (3); grade 3 and 4 events were limited to AST/ALT elevations (3). TRAE occurring in more than 1 patient in the Asia were diarrhea (5), AST/ALT elevation (4), ALP elevation (3), fatigue (3), nausea (2), vomiting (2), dizziness (2), and headache (2). No grade 3 and 4 events reported. Out of 9 evaluable pts in the US, 1 pt with HCC achieved a partial response (ongoing at 12 months) and 5/9 pts had stable disease (SD), 4 of which lasted ≥4 months. In Asia, 4 out of 6 evaluable patients had SD and 1 lasted ≥10 months. AU409 showed approximately dose-proportional systemic exposure. Paired biopsies from 3 HCC pts at 300 mg showed downregulation of multiple TATA-regulated transcripts, including MYC , AFP , CCL20 , and other genes involved in chemokines, heat-shock proteins, and cell-cycle, in line with preclinical data. The greatest transcriptional suppression occurred in the pt with PR. Conclusions: AU409, a novel transcription regulator, has a manageable safety profile in two ongoing phase I studies. The partial response and prolonged stability in pts with HCC who have progressed on one or more prior lines of therapy is encouraging and consistent with preclinical data. Exploratory evidence of transcriptional downregulation in tumor samples provides early proof-of-concept about the mechanism of AU409. Accrual continues in both trials.