PO.CTP01.02 · 进行中的临床试验
中枢神经系统（CNS）穿透性、PARP1选择性抑制剂EIK1004治疗伴或不伴脑转移的晚期实体瘤患者的首次人体（FIH）1/2期剂量递增和剂量优化研究
A first-in-human (FIH), Phase 1/2, dose-escalation and dose-optimization study of central nervous system (CNS)-penetrant, PARP1-selective inhibitor EIK1004 in patients with advanced solid tumors with or without brain metastases
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摘要 Abstract
中文摘要
背景：PARP抑制剂（PARPi）选择性杀伤携带关键DNA修复基因（如BRCA1/2）遗传突变的肿瘤细胞。已获批的非选择性PARPi已展现出强劲的抗肿瘤活性，但与显著的血液学毒性相关，从而限制了剂量强度和临床获益。选择性抑制PARP1但不影响PARP2的药物可能通过保留抗肿瘤活性同时避免PARP2相关毒性来改善风险-获益特征。此外，现有PARPi的脑穿透性各异，限制了它们靶向CNS肿瘤或脑转移的效用。EIK1004（IMP1707）是一种强效、CNS穿透性、PARP1选择性抑制剂，在临床前脑转移模型中展现出肿瘤生长抑制作用。
方法：研究EIK1004-001（IMP1707-101）是一项FIH、全球、多中心1/2期研究，评估EIK1004单药治疗在伴或不伴脑转移的晚期卵巢癌、乳腺癌、前列腺癌或胰腺癌患者中的安全性和潜在抗肿瘤活性（NCT06907043）。该研究包括第1部分（剂量递增；采用贝叶斯最优区间[BOIN]设计）和第2部分（剂量优化）。所有参与者必须在选定的同源重组修复基因中携带有害或疑似有害突变，且既往接受不超过一线PARPi治疗。符合条件的参与者必须年龄≥18岁，具有组织学或细胞学确诊的肿瘤，接受过适当的既往抗肿瘤治疗，并有可评估疾病（例如，根据RECIST 1.1至少有1个可测量病灶[脑转移则根据RANO-BM]和/或血清肿瘤标志物）。主要终点包括安全性和耐受性，包括确定最大耐受剂量或最大可达剂量，以及推荐的扩展剂量（RDE）。次要终点包括评估EIK1004的药代动力学和初步抗肿瘤活性，包括总缓解率、缓解持续时间和无进展生存期。第2部分将在第1部分确定RDE后启动。该研究于2025年1月23日启动，正在积极入组参与者。
查看英文原文 English abstract
Background: PARP inhibitors (PARPi) selectively kill tumor cells harboring genetic mutations in critical DNA repair genes (e.g., BRCA1/2). Approved nonselective PARPi have demonstrated robust antitumor activity, but are associated with significant hematologic toxicities that limit dose intensity and clinical benefit. Drugs that selectively inhibit PARP1, but spare PARP2, may improve the risk-benefit profile by retaining antitumor activity while avoiding PARP2-related toxicities. Furthermore, current PARPi have variable brain penetrance, limiting their utility for targeting CNS tumors or brain metastases. EIK1004 (IMP1707) is a potent, CNS-penetrant, PARP1-selective inhibitor that demonstrates tumor growth inhibition in preclinical brain metastasis models.
Methods: Study EIK1004-001 (IMP1707-101) is a FIH, global, multi-center, Phase 1/2 study evaluating the safety and potential antitumor activity of EIK1004 monotherapy in patients with advanced ovarian, breast, prostate, or pancreatic cancer, with or without brain metastases (NCT06907043). The study consists of Part 1 (Dose Escalation; using the Bayesian optimal interval [BOIN] design) and Part 2 (Dose Optimization). All participants must have a deleterious or suspected deleterious mutation in select homologous recombination repair genes and received no more than one prior line of PARPi treatment. Eligible participants must be ≥ 18 years, have histologically or cytologically confirmed tumors and received appropriate prior antitumor therapies, and have evaluable disease (eg, at least 1 measurable lesion by RECIST 1.1 [or RANO-BM for brain metastases] and/or serum tumor markers). Primary endpoints include safety and tolerability including identifying the maximum tolerated dose or maximum achievable dose, and recommended dose(s) for expansion (RDE). Secondary endpoints include evaluation of EIK1004 pharmacokinetics and preliminary antitumor activity including overall response, duration of response, and progression-free survival. Part 2 will open once the RDE is determined from Part 1. This study opened on 23-Jan-2025 and is actively enrolling participants.
利益披露 Disclosure
T. A. Yap,
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