POLQ抑制剂SYN818联合奥拉帕利（olaparib）治疗晚期实体瘤的Ib期研究

Background: SYN818 is a selective, potent oral POLQ helicase inhibitor. POLQ is essential for microhomology-mediated end-joining and fills single-stranded DNA (ssDNA) gaps during replication. In tumors with homologous recombination repair (HRR) deficiencies (e.g., BRCA1/2 mutations), inhibition of PARP creates a dependency on POLQ for ssDNA gap filling, providing a synthetic lethal therapeutic strategy. Preclinically, SYN818 significantly enhanced the antitumor activity of Olaparib in breast and ovarian cancer models. Phase 1a monotherapy data demonstrate that SYN818 has a favorable pharmacokinetic profile and is well tolerated, supporting further evaluation of SYN818 in combination with Olaparib in HRR-deficient metastatic solid tumors. Trial design: This phase 1b, open-label, multicenter study (NCT07156253; CTR20253189) evaluates SYN818 in combination with Olaparib in adults with locally advanced or metastatic solid tumors harboring BRCA mutations and/or homologous recombination repair (HRR) deficiency. During dose escalation (Part 1), patients receive escalating doses of SYN818 in combination with Olaparib (300 mg BID) administered in 21-day cycles to determine the recommended Phase 2 dose (RP2D), guided by a Bayesian dose-finding model. In the dose-expansion phase (Part 2), tumor-specific cohorts, including ovarian cancer and HER2-negative breast cancer, will further assess safety and preliminary antitumor activity at the RP2D. The primary objectives are to evaluate safety, tolerability, and determine the RP2D. Secondary objectives include characterization of pharmacokinetics, pharmacodynamics, and preliminary antitumor activity per RECIST v1.1. Key eligibility criteria include age ≥18 years, ECOG performance status 0-1, documented BRCA mutation and/or HRR deficiency, and adequate organ function. Prior PARP inhibitor therapy is permitted. Enrollment initiated in September 2025.