Abstract CT288: First-in-human study of oral PARG inhibitor SYN608 in advanced solid tumors

Abstract Background: SYN608 is a novel, selective, orally bioavailable poly (ADP-ribose) glycohydrolase (PARG) inhibitor. PARG plays a critical role in the DNA damage response by reversing protein PARylation and maintaining dynamic balance with PARP activity. Inhibition of PARG results in accumulation of PAR chains, leading to impaired DNA replication and repair and inducing synthetic lethality in tumors with homologous recombination (HR) deficiencies. This mechanism provides a potential strategy to overcome resistance to PARP inhibitors. Preclinically, SYN608 has demonstrated robust antitumor activity in models of DNA damage repair (DDR) deficient tumors, supporting its clinical evaluation in patients with advanced solid tumors harboring HR defects. Trial design: This is a first-in-human, phase I, open-label, multicenter study (NCT07088588; CTR20252846) evaluating SYN608 monotherapy in adult patients with locally advanced or metastatic solid tumors who have exhausted standard therapies. The study includes a Bayesian model-guided dose-escalation phase to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), with oral administration of SYN608 in 21-day cycles. Following RP2D determination, a dose-expansion phase will enroll biomarker-selected cohorts with documented DNA damage response (DDR) deficiencies, including BRCA mutations, to further evaluate safety and preliminary antitumor activity. Primary objectives are to assess safety, tolerability, and define the RP2D; secondary objectives include pharmacokinetics, pharmacodynamics, and antitumor activity per RECIST v1. 1. Key inclusion criteria include age ≥18 years, ECOG performance status 0-1, measurable advanced solid tumors, and documented homologous recombination deficiency. Prior PARP inhibitor therapy is permitted, while prior treatment with a PARG inhibitor is excluded. Enrollment initiated in August 2025. Citation Format: Jin Li, Xiaohua Wu, Qi Dang, Ke Wang, Zhengbo Song, Jun Zhou, Yujia Zhang, Jian Zhang, Jiajia Li, Weina Shen, Shengjie Yang, Hongli Li, Lu Sun, Liyan Zhou, Jianan Jin, Duo Wu, Yue Xie, Xuzhen Tang, Chao Kan, Song Shi, Hu He, Song Liu, Xiaochun Yu. First-in-human study of oral PARG inhibitor SYN608 in advanced solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT288.