Abstract CT152: A phase I study of POLQ inhibitor SYN818 as monotherapy in adult patients with locally advanced or metastatic solid tumors

Abstract Objective: DNA double-strand breaks are severely damaging genomic lesions. They can be repaired via homologous recombination, non-homologous end-joining, and microhomology-mediated end-joining (MMEJ), with DNA polymerase theta (POLQ) being crucial for MMEJ. POLQ also fills single-stranded DNA (ssDNA) gaps during or after replication. When cells have mutations in BRCA1, BRCA2, and RAD51 (involved in ssDNA gap handling), PARP1-mediated PARylation and POLQ take over ssDNA gap filling. Thus, inhibiting POLQ, alone or with PARPi, can kill tumor cells lacking key ssDNA gap-filling factors. SYN818 is a selective and potent oral POLQ inhibitor. Preclinical studies show that SYN818 exhibits excellent efficacy, pharmacokinetic (PK) properties, and safety profiles, both as a monotherapy and in combination with PARPi. This first-in-human study assesses SYN818 in solid tumor patients. Methods: This Phase I (NCT06666270), open-label, multicenter, dose-escalation study evaluates the safety, tolerability, PK, and preliminary anti-tumor efficacy of SYN818 as monotherapy in advanced solid tumor patients. The primary endpoints are safety and maximum-tolerated dose. Secondary endpoints include PK, objective response rate, and survival metrics. Dose escalation follows Bayesian Optimal Interval design, enrolling ∼30 patients. Eligible patients are aged ≥18 years with advanced solid tumors, ECOG PS 0-1, ≥3 months life expectancy, ≥ 1 measurable lesion, and adequate organ function. Exclusions are prior treatment-related adverse events (TEAEs) not resolved, uncontrolled brain or leptomeningeal metastases, prior POLQ inhibitor use, or a second malignancy in the past 2 years. A Phase Ib/II trial will assess SYN818 in combination with PARPi in patients with locally advanced or metastatic solid tumors harboring BRCA or homologous recombination repair (HRR) mutations. Results: As of February 12, 2025, four patients with solid tumors had been enrolled and received SYN818 across two dose levels (50 mg, n=1; 100 mg, n=3). Neither dose-limiting toxicities (DLTs) nor SYN818-related G3/4 treatment-emergent adverse events (TEAEs) were observed. The most common AEs were grade 1 (nausea, 2/4; fatigue, 3/4), with no grade ≥2 treatment-related AEs observed. The PK profiles of SYN818 not only aligned closely with the predicted human PK profiles but also exceeded the expectations derived from preclinical studies, indicating a more favorable outcome. Across the first two dose levels, systemic exposure increased linearly. Furthermore, the initial PK profiles at these dose levels demonstrate adequate target coverage, supporting continued evaluation in the Phase I trial. Conclusion: SYN818 has exhibited a favorable safety profile and PK characteristics when administered as a single agent at doses up to 100 mg. The preliminary safety profile supports its potential value in combination with PARPi and/or rational therapeutics modalities. As of the cut-off date, the MTD has not been reached, and enrollment is ongoing. Citation Format: Yiqun Du, Hongxia Wang, Min Yan, Tongfu Xu, Yue Xie, Duo Wu, Xuzhen Tang, Chao Kan, Song Shi, Hu He, Song Liu, Xiaochun Yu. A phase I study of POLQ inhibitor SYN818 as monotherapy in adult patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT152.