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. This article is featured in Highlights of This Issue, [p. 4945][1] [1]: /lookup/volpage/27/4945?iss=18

中文翻译：

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Telaglenastat 在晚期或转移性实体瘤患者中的 I 期剂量递增和扩展研究

目的：谷氨酰胺是实体瘤的重要燃料。在临床前模型中，干扰谷氨酰胺代谢对瘤形成是有害的。在治疗难治性实体瘤患者中进行了口服一流谷氨酰胺酶 (GLS) 抑制剂 telaglenastat 的 I 期研究，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：通过 3 + 3 设计进行剂量递增，然后是探索性肿瘤/生物标志物特异性队列。结果：在 120 名患者中，疲劳 (23%) 和恶心 (19%) 是最常见的毒性。未达到最大耐受剂量。相关分析表明，在血浆暴露 >300 nmol/L 时，血小板中的 GLS 抑制 >90%，肿瘤 GLS 抑制 >75%，并且循环谷氨酰胺显着增加。RP2D 定义为每天两次 800 mg。扩展队列中的疾病控制率 (DCR) 为 43%（总体缓解率为 5%，肾细胞癌的 DCR 为 50%）。结论：Telaglenastat 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。这篇文章刊登在本期要闻中，[p。4945][1][1]:/lookup/volpage/27/4945?iss=18