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1b/2期临床试验及相关分析

原文发布日期：2024-09-19

英文摘要：

摘要翻译：

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文章：

1b/2期临床试验及相关分析

a phase 1b/2 clinical trial and correlative analyses

原文发布日期：2024-09-19

英文摘要：

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993.

摘要翻译：

恶性肿瘤依赖谷氨酰胺作为能量来源，并促进异常DNA甲基化。我们展示了telaglenastat（CB-839）联合azacytidine（AZA）的前临床协同作用，随后在患有骨髓增生综合征晚期的单臂、开放标签、1b/2期研究中进行了评估。研究的主要终点包括临床活性、安全性和耐受性；次要终点包括药代动力学、总生存率、无进展生存率和应答持续时间。剂量递进研究纳入了6名参与者，而剂量扩大研究则纳入了24名参与者。治疗耐受性良好，并且70%的参与者出现了临床反应，其中53%实现了完全血清素减少（BM）。研究中患者的中位总生存期为11.6个月，单细胞RNA测序证实了应答者的髓系分化特征。骨髓增生综合征干细胞中的谷氨酰胺转运体家族成员38成员1与临床反应相关，并在大规模MDS队列中预测了更差的预后。这些数据表明CB-839和AZA联合使用是一种在MDS中具有安全性和有效性的代谢和表观遗传学方法。临床Trials.gov标识符：NCT03047993。