在晚期或转移性实体瘤患者中进行的 Telaglenastat 的 I 期剂量递增和扩展研究。
A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors.
机构信息
Memorial Sloan Kettering Cancer Center and Weill Medical College, New York, New York.
Stanford University School of Medicine, Stanford, California.
出版信息
Clin Cancer Res. 2021 Sep 15;27(18):4994-5003. doi: 10.1158/1078-0432.CCR-21-1204. Epub 2021 Jul 20.
PURPOSE
Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) inhibitor telaglenastat was conducted in treatment-refractory solid tumor patients to define recommended phase II dose (RP2D) and evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.
PATIENTS AND METHODS
Dose escalation by 3 + 3 design was followed by exploratory tumor-/biomarker-specific cohorts.
RESULTS
Among 120 patients, fatigue (23%) and nausea (19%) were the most common toxicity. Maximum tolerated dose was not reached. Correlative analysis indicated >90% GLS inhibition in platelets at plasma exposures >300 nmol/L, >75% tumoral GLS inhibition, and significant increase in circulating glutamine. RP2D was defined at 800 mg twice-daily. Disease control rate (DCR) was 43% across expansion cohorts (overall response rate 5%, DCR 50% in renal cell carcinoma).
CONCLUSIONS
Telaglenastat is safe, with a favorable PK/PD profile and signal of antitumor activity, supporting further clinical development.
目的
谷氨酰胺是实体瘤的关键燃料。在临床前模型中，干扰谷氨酰胺代谢对肿瘤是有害的。一项关于口服、首创的谷氨酰胺酶（GLS）抑制剂替拉那斯特的 I 期研究在治疗难治性实体瘤患者中进行，以确定推荐的 II 期剂量（RP2D）并评估安全性、药代动力学（PK）、药效学（PD）和抗肿瘤活性。
患者和方法
采用 3+3 设计进行剂量递增，然后进行探索性肿瘤/生物标志物特异性队列研究。
结果
在 120 名患者中，最常见的毒性是疲劳（23%）和恶心（19%）。未达到最大耐受剂量。相关性分析表明，在血浆暴露>300 nmol/L 时，血小板中的 GLS 抑制率>90%，肿瘤中的 GLS 抑制率>75%，并显著增加了循环中的谷氨酰胺。确定 800 mg 每日两次的剂量为 RP2D。扩展队列的疾病控制率（DCR）为 43%（整体反应率为 5%，肾细胞癌的 DCR 为 50%）。
结论
替拉那斯特是安全的，具有良好的 PK/PD 特征和抗肿瘤活性信号，支持进一步的临床开发。
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