Krishnamurthy Anuradha, Wang Hong, Rhee John C, Davar Diwakar, Moy Ryan H, Ratner Lee, Christner Susan M, Holleran Julianne L, Deppas Joshua, Sclafani Carina, Schmitz John C, Gore Steve, Chu Edward, Bakkenist Christopher J, Beumer Jan H, Villaruz Liza C
Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Cancer Chemother Pharmacol. 2025 Jan 22;95(1):27. doi: 10.1007/s00280-024-04745-6.
ATR is an apical DDR kinase activated at damaged replication forks. Elimusertib is an oral ATR inhibitor and potentiates irinotecan in human colorectal cancer models.
To establish dose and tolerability of elimusertib with FOLFIRI, a Bayesian Optimal Interval trial design was pursued. Starting elimusertib dose was 20 mg BID days 1, 2, 15 and 16 every 28-day cycle, combined with irinotecan (150 mg/m) and 5-FU (2000 mg/m).
The trial was stopped after 10 accruals, with four DLT across 4 dose levels including grade 3 febrile neutropenia, mucositis, nausea, vomiting and grade 4 neutropenia. The most common grade 3/4 adverse events were neutropenia, leukopenia, lymphopenia and mucositis. Based on significant toxicities the trial was stopped. PK data for 5-FU and irinotecan were unremarkable and did not account for DLTs. Among the six response evaluable patients, four had stable disease as their best response. Median PFS was 7 months. A first case of ATRi chemotherapy combination related AML (t-AML) was observed.
The combination of elimusertib with FOLFIRI was associated with intolerable toxicity. Combination of ATR kinases with chemotherapies that target DNA replication may be associated with significant myelotoxicity. Ongoing ATRi trials should monitor for t-AML.
NCT04535401.
ATR是一种在受损复制叉处被激活的顶端DNA损伤反应激酶。埃利穆塞替布是一种口服ATR抑制剂，在人结直肠癌模型中可增强伊立替康的疗效。
为确定埃利穆塞替布与FOLFIRI联合使用的剂量和耐受性，采用了贝叶斯最优区间试验设计。每28天为一个周期，第1、2、15和16天埃利穆塞替布起始剂量为20mg，每日两次，联合伊立替康（150mg/m²）和5-氟尿嘧啶（2000mg/m²）。
在纳入10例患者后试验停止，4个剂量水平共出现4例剂量限制性毒性，包括3级发热性中性粒细胞减少、粘膜炎、恶心、呕吐和4级中性粒细胞减少。最常见的3/4级不良事件是中性粒细胞减少、白细胞减少、淋巴细胞减少和粘膜炎。基于显著的毒性反应，试验停止。5-氟尿嘧啶和伊立替康的药代动力学数据无异常，且不能解释剂量限制性毒性。在6例可评估反应的患者中，4例最佳反应为病情稳定。中位无进展生存期为7个月。观察到首例与ATR抑制剂化疗联合相关的急性髓系白血病（t-AML）。
埃利穆塞替布与FOLFIRI联合使用具有无法耐受的毒性。ATR激酶与靶向DNA复制的化疗药物联合使用可能会导致显著的骨髓毒性。正在进行的ATR抑制剂试验应监测t-AML。
NCT04535401。
