PO.CTP01.02 · 进行中的临床试验
NTS071-101：一项评估NTS071在携带TP53 Y220C突变的晚期实体瘤患者中安全性、耐受性、药代动力学和初步疗效的1/2a期研究
NTS071-101: A phase 1/2a study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of NTS071 in patients with advanced solid tumors harboring a TP53 Y220C mutation
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摘要 Abstract
中文摘要
背景：TP53基因编码一种肿瘤抑制蛋白，该蛋白结合DNA并转录激活一个负责细胞周期检查点、凋亡、DNA修复及其他细胞过程的靶基因网络。在约半数癌症病例中，p53蛋白的正常功能被不同突变所失活。Y220C是一种常见的TP53错义突变，全球每年影响约100,000例新发癌症病例。NTS071是一种新型小分子，旨在选择性结合并稳定TP53 Y220C突变蛋白，恢复野生型p53功能。在临床前研究中，NTS071相比PC14586（一种具有相同靶向机制的在研药物）展现出更优的体外效力、良好的ADME/T特征以及增强的体内抗肿瘤疗效。目前尚无靶向TP53 Y220C的疗法获批，凸显了显著的未满足医疗需求。
方法：NTS071-101是一项首次人体、开放标签、多中心1/2a期研究，针对既往标准治疗失败的TP53 Y220C突变晚期实体瘤患者设计。该研究包括两个部分：1期（带回填的剂量递增）和2a期（剂量优化）。1期对100和200 mg剂量水平采用加速滴定设计，随后采用带回填的贝叶斯最优区间（BOIN）设计。剂量递增阶段的计划剂量水平包括100、200、400、800、1200、1600和2000 mg，以21天为治疗周期每日口服一次（QD）。1期的主要目的是评估安全性和耐受性，并确定最大耐受剂量（MTD）。次要目的包括药代动力学（PK）表征和初步疗效评估。2a期研究旨在评估NTS071的初步临床疗效。次要目的包括进一步表征其疗效特征、确定推荐的2b期剂量（RP2bD）、评估安全性以及PK表征。探索性目的是评估NTS071的药效动力学特征、疗效结局与相关生物标志物之间的相关性。
总结：NTS071的首次人体试验标志着为治疗选择有限、预后不良的患者推进此类精准肿瘤学疗法的一个关键里程碑。NTS071-101的首例患者于2025年8月入组，目前正在美国和中国持续积极招募。
查看英文原文 English abstract
Background: The TP53 gene encodes a tumor suppressor that binds to DNA and transcriptionally activates a network of target genes responsible for cell-cycle checkpoint, apoptosis, DNA repair, and other cellular processes. The normal function of p53 protein is inactivated by different mutations in about half of all cancer cases. Y220C is a prevalent TP53 missense mutation affecting approximately 100,000 new cancer cases per year worldwide. NTS071 is a novel small molecule designed to selectively bind and stabilize TP53 Y220C mutant protein, restoring wild type p53 function. In preclinical studies, NTS071 has demonstrated superior in vitro potency, favorable ADME/T profile, and enhanced in vivo antitumor efficacy versus PC14586 (an investigational drug with the same targeting mechanism). No therapies targeting TP53 Y220C are currently approved, highlighting the significant unmet medical need.
Methods: NTS071-101 is a first-in-human, open-label, multi-center phase 1/2a study designed for patients with TP53 Y220C-mutated advanced solid tumors who have failed standard therapies. The study comprises two parts: phase 1 (dose escalation with backfilling) and phase 2a (dose optimization). Phase 1 employs an accelerated titration design for 100 and 200 mg dose levels, followed by Bayesian Optimal Interval (BOIN) design with backfilling. The planned dose levels for the dose escalation stage include 100, 200, 400, 800, 1200, 1600, and 2000 mg, administered orally once daily (QD) in 21‑day treatment cycles. The primary objectives of phase 1 are to evaluate the safety and tolerability, and to determine the Maximum Tolerated Dose (MTD). Secondary objectives include pharmacokinetic (PK) profiling and preliminary efficacy assessment. The phase 2a study aims to evaluate the preliminary clinical efficacy of NTS071. Secondary objectives include further characterization of its efficacy profile, determination of the Recommended Phase 2b Dose(s) (RP2bD), assessment of safety, and PK profiling. Exploratory objectives are to evaluate the correlations between NTS071's pharmacodynamic profiles, efficacy outcomes, and relevant biomarkers.
Summary: The first-in-human trial of NTS071 marks a critical milestone in advancing such precision oncology therapies for those patients with limited treatment options and poor prognosis. The first patient for NTS071-101 enrolled in August 2025, with active recruitment continuing in both the U.S. and China.
利益披露 Disclosure
Q. Shen, None..
Y. Xu, None..
Y. Wu, None..
S. Shen, None..
G. Zhou, None.