Tsimberidou Apostolia M, Dayyani Farshid, Sommerhalder David, Vandross Andrae L, Pelster Meredith S, Henry Jason T, Perez Cesar A, Chakraborty Abhijit, Baysal Mehmet A, Chandhasin Chandtip, Dai Yiyun, Tu Shirley, King Ivan, Perabo Frank
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Chao Family Comprehensive Cancer Center, University of California at Irvine, Orange, CA, USA.
Oncologist. 2025 Jul 4;30(7). doi: 10.1093/oncolo/oyaf169.
This was a first-in-human, phase I, dose-escalation study evaluating the safety, pharmacokinetics, and preliminary efficacy of zavondemstat (TACH101), an epigenetic targeting inhibitor of KDM4 histone demethylase, in patients with heavily pre-treated advanced/metastatic cancers.
Patients received zavondemstat orally on a weekly schedule in 28-day cycles. Dose escalation followed a Bayesian optimal interval design and explored both intermittent and continuous dosing. The primary objectives were to assess safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase II dose (RP2D). Secondary objectives included pharmacokinetics and radiographic response per Response Evaluation Criteria in Solid Tumors, version 1.1.
Thirty patients were enrolled across 6 dose cohorts. MTD was not reached at the maximum dose tested. The most common treatment-related adverse events (TRAEs) were diarrhea (12%), fatigue (7%), decreased appetite (7%), nausea (7%), and hyponatremia (7%). All TRAEs were grade 1 or 2. No serious TRAEs or DLTs were reported. Of 23 response-evaluable patients, 10 (44%) achieved stable disease (SD). Two patients (9%) had SD ≥ 6 months, including a patient with castration-resistant prostate cancer and a patient with leiomyosarcoma. A third patient (leiomyosarcoma) receiving ongoing treatment with zavondemstat under compassionate use has had SD for 6+ months. Zavondemstat demonstrated a dose-proportional exposure profile with a half-life of about 1.5 hours. There was no to minimal drug accumulation observed.
Zavondemstat was very well tolerated and showed encouraging preliminary clinical benefit in heavily pretreated patients with advanced cancer. Continued evaluation of zavondemstat is warranted.
这是一项首次在人体进行的I期剂量递增研究，旨在评估zavondemstat（TACH101），一种KDM4组蛋白去甲基化酶的表观遗传靶向抑制剂，在经过大量前期治疗的晚期/转移性癌症患者中的安全性、药代动力学和初步疗效。
患者在28天周期内每周口服一次zavondemstat。剂量递增遵循贝叶斯最优间隔设计，探索了间歇给药和持续给药两种方式。主要目标是评估安全性、剂量限制性毒性（DLT）、最大耐受剂量（MTD）和推荐的II期剂量（RP2D）。次要目标包括药代动力学以及根据实体瘤疗效评价标准1.1版评估的影像学反应。
30名患者入组了6个剂量组。在测试的最大剂量下未达到MTD。最常见的治疗相关不良事件（TRAE）为腹泻（12%）、疲劳（7%）、食欲下降（7%）、恶心（7%）和低钠血症（7%）。所有TRAE均为1级或2级。未报告严重TRAE或DLT。在23名可评估反应的患者中，10名（44%）达到疾病稳定（SD）。两名患者（9%）的SD持续≥6个月，包括一名去势抵抗性前列腺癌患者和一名平滑肌肉瘤患者。第三名接受zavondemstat同情用药持续治疗的患者（平滑肌肉瘤）SD已持续6个月以上。Zavondemstat表现出剂量成正比的暴露特征，半衰期约为1.5小时。未观察到药物蓄积或仅有极少的药物蓄积。
Zavondemstat耐受性良好，在经过大量前期治疗的晚期癌症患者中显示出令人鼓舞的初步临床获益。有必要对zavondemstat继续进行评估。
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