PO.CT01.02 · 临床试验

ACE-106（一种高选择性、潜在同类最优的PARP1抑制剂）治疗晚期实体瘤的首次人体1/2期研究更新结果

Updated results from a first-in-human phase 1,2 study of ACE-106, a highly selective and potentially best-in-class PARP1 inhibitor in advanced solid tumors

编号 CT064 展板 24 时间 4/20 09:00–12:00 区域 Section 50 主讲 Kuo-Long Yu, PhD

分会场 First-in-Human Phase I Clinical Trials

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作者与单位 Authors & Affiliations

Xingyun Cai¹, Jian Zhang², Yu Chen³, Yanxia Shi⁴, Wei Wang⁵, Zhanhong Chen⁶, Jiongjie Chen¹

¹Acerand Therapeutics (Hong Kong) Limited, Shanghai, China,²Fudan University Shanghai Cancer Center, Shanghai, China, Shanghai, China,³Fujian Cancer Hospital, Fuzhou, China,⁴Sun Yat-sen University Cancer Center, Guangzhou, China, Guangzhou, China,⁵Shanxi Medical University Second Hospital, Taiyuan, China, Taiyuan, China,⁶Zhejiang Cancer Hospital, Hangzhou, China, Hangzhou, China

摘要 Abstract

中文摘要

背景：ACE-106（ACE-86225106）是一种高选择性PARP1抑制剂，旨在相对于第一代泛PARP抑制剂改善治疗指数。本文报告首次人体研究（NCT06380660）的更新数据。方法：该研究包括一个"3+3"剂量递增模块和一个回填模块。晚期或转移性实体瘤患者（pts）接受ACE-106单药每日一次口服。回填模块入组要求存在胚系或体细胞HRR突变（HRRm），包括BRCA1/2、PALB2或CDK12突变，而剂量递增模块允许无HRRm的患者入组。主要目的为安全性；次要目的为PK、药效学和初步疗效。结果：截至数据截止日（2025年12月31日），52例患者接受了剂量范围为5-80 mg的ACE-106治疗，中位治疗持续时间为2.1（范围0.6-18.4）个月。患者既往系统治疗中位数为4线（范围1-12），29%既往接受过PARPi。ACE-106在所有剂量水平下耐受性良好，无剂量限制性毒性，无4-5级治疗相关不良事件（TRAE）。未报告导致剂量降低或停药的TRAE。17%的患者发生3级TRAE，最常见为贫血（10%）、血小板计数降低（2%）、淋巴细胞计数降低（2%）、食欲下降（2%）和呕吐（2%）。血液学毒性未随剂量水平升高而增加。在16例可按RECIST1.1标准评估影像学缓解的HRRm患者中，客观缓解率（ORR）为38%（6/16），最长缓解持续时间为12个月；疾病控制率（DCR）为75%（12/16）。值得注意的是，在HRRm转移性去势抵抗性前列腺癌（mCRPC）患者中，ORR为50%（4/8），PSA50缓解率为42%（5/12）。1例无HRRm的mCRPC患者也达到确认的部分缓解。在泛PARPi初治的晚期卵巢癌（OC）患者中，ORR为67%（2/3），DCR为100%。ACE-106在全部6个剂量下表现出平坦的PK曲线（Cmax为Cmin的1.4-2.3倍），平均T1/2为20.6-34.5小时，支持每日一次给药。药物暴露随剂量成比例增加，在80mg每日一次时观察到Cmin与靶有效浓度（TEC）之比高达69倍。结论：ACE-106在既往接受过大量治疗的晚期实体瘤中耐受性良好，显示出有前景的疗效和优异的PK特性。其临床特征提示具有取代泛PARPi的同类最优选择性PARP1i潜力，并支持进一步开发基于ACE-106的联合治疗。声明：本摘要使用生成式AI协助修订作者撰写的内容。

查看英文原文 English abstract

Background: ACE-106 (ACE-86225106) is a highly selective PARP1 inhibitor designed to improve the therapeutic index relative to first-generation pan-PARP inhibitors. Here, we report the updated data from the first-in-human study (NCT06380660). Method: The study comprises a “3+3” dose escalation module and a backfill module. Patients (pts) with advanced or metastatic solid tumors were treated with ACE-106 monotherapy QD PO. Enrollment in the backfill module required germline or somatic HRR mutations (HRRm), including BRCA1/2, PALB2, or CDK12 mutations, while the dose escalation module allowed pts without HRRm. The primary objective was safety; secondary objectives were PK, pharmacodynamics, and preliminary efficacy. Result: As data cut-off (Dec 31, 2025), 52 pts received ACE-106 at dose levels ranging from 5-80 mg, with a median treatment duration of 2.1 (range 0.6-18.4) months. The pts had a median 4 (range 1-12) lines of prior systemic therapy, and 29% had prior PARPi. ACE-106 was well tolerated across all dose levels, with no dose-limiting toxicities or grade 4-5 treatment-related adverse events (TRAEs). No TRAEs leading to dose reduction or discontinuation were reported. Grade 3 TRAEs occurred in 17% of pts, with the most common being anemia (10%), decreased platelet count (2%), decreased lymphocyte count (2%), decreased appetite (2%), and vomiting (2%). Hematological toxicity did not increase along with the dose level. Among 16 pts with HRRm evaluable for radiological response per RECIST1.1 criteria, objective response rate (ORR) was 38% (6/16) with the longest duration of response of 12 months; and disease control rate (DCR) was 75% (12/16). Notably, among metastatic castration-resistant prostate cancer (mCRPC) pts with HRRm, ORR was 50% (4/8) and PSA50 response rate was 42% (5/12). One mCRPC pt without HRRm also had a confirmed partial response. Among advanced ovarian cancer (OC) pts who were naïve to pan-PARPi, ORR was 67% (2/3) and DCR was 100%. ACE-106 demonstrated a flat PK curve (Cmax was 1.4-2.3 fold of Cmin) across all 6 doses, with a mean T 1/2 of 20.6-34.5 hours supporting QD dosing. Drug exposure increased proportionally with dose, and up to 69 fold of Cmin to target effective concentration (TEC) ratio was observed at 80mg QD. Conclusion: ACE-106 was well tolerated and showed promising efficacy and excellent PK properties in heavily pre-treated advanced solid tumors. The clinical profile suggests a best-in-class selective PARP1i potential to replace pan-PARPi and justify further development of ACE-106-based combination therapy. Disclosure: This abstract used generative AI to help revise content written by authors.

利益披露 Disclosure

X. Cai, Acerand Therapeutics (Hong Kong) Limited Employment. J. Zhang, None.. Y. Chen, None.. Y. Shi, None.. W. Wang, None.. Z. Chen, None. J. Chen, Acerand Therapeutics (Hong Kong) Limited Employment.

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