Phase I trial of ATR inhibitor elimusertib with FOLFIRI in advanced or metastatic gastrointestinal malignancies (ETCTN 10406).

IF 2.7 4区医学 Q3 ONCOLOGY

Cancer Chemotherapy and Pharmacology Pub Date : 2025-01-22 DOI:10.1007/s00280-024-04745-6

Anuradha Krishnamurthy, Hong Wang, John C Rhee, Diwakar Davar, Ryan H Moy, Lee Ratner, Susan M Christner, Julianne L Holleran, Joshua Deppas, Carina Sclafani, John C Schmitz, Steve Gore, Edward Chu, Christopher J Bakkenist, Jan H Beumer, Liza C Villaruz

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引用次数: 0

Abstract

Background: 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.

Methods: 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/m²) and 5-FU (2000 mg/m²).

Results: 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.

Conclusions: 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.

Clinicaltrials:

Gov id: NCT04535401.

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ATR抑制剂elimusertib联合FOLFIRI治疗晚期或转移性胃肠道恶性肿瘤的I期临床试验（ETCTN 10406）。

背景：ATR是在受损的复制分叉处激活的顶端DDR激酶。Elimusertib是一种口服ATR抑制剂，在人类结直肠癌模型中增强伊立替康。方法：采用贝叶斯最优间隔试验设计，建立elimusertib与FOLFIRI的剂量和耐受性。起始剂量为20mg， BID第1、2、15和16天，每28天一个周期，联合伊立替康（150mg /m2）和5-FU （2000mg /m2）。结果：试验在10次累积后停止，4次DLT在4个剂量水平，包括3级发热性中性粒细胞减少症、粘膜炎、恶心、呕吐和4级中性粒细胞减少症。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，试验被终止。5-FU和伊立替康的PK数据不显著，不考虑dlt。在6例反应可评估的患者中，4例病情稳定为最佳反应。中位PFS为7个月。观察到第一例ATRi联合化疗相关AML （t-AML）。结论：elimusertib与FOLFIRI合用具有不可耐受的毒性。ATR激酶联合靶向DNA复制的化疗可能与显著的髓毒性有关。正在进行的ATRi试验应该监测t-AML。临床试验：政府编号：NCT04535401。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Chemotherapy and Pharmacology 医学-药学

CiteScore

6.10

自引率

3.30%

发文量

116

审稿时长

2.5 months

期刊介绍： Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.