一项关于 crenigacestat（LY3039478）联合吉西他滨和顺铂或吉西他滨和卡铂治疗晚期或转移性实体瘤患者的 1b 期研究。
A phase 1b study of crenigacestat (LY3039478) in combination with gemcitabine and cisplatin or gemcitabine and carboplatin in patients with advanced or metastatic solid tumors.
机构信息
Drug Development Department (DITEP), Inserm Unit U981, Universite´ Paris Saclay, Universite´ Paris-Sud, Gustave Roussy, Villejuif, France.
Department of Medicinal Oncology, Centre Léon Bérard, Lyon, France.
出版信息
Cancer Chemother Pharmacol. 2022 Oct;90(4):335-344. doi: 10.1007/s00280-022-04461-z. Epub 2022 Aug 28.
BACKGROUND
Notch signaling plays an integral role in development and tissue homeostasis. Inhibition of Notch signaling has been identified as a reasonable target for oncotherapy. Crenigacestat (LY3039478) is a potent Notch inhibitor that decreases Notch signaling and its downstream biologic effects.
METHODS
I6F-MC-JJCD was a multicenter, nonrandomized, open-label, phase 1b study with 5 separate, parallel dose escalations in patients with advanced or metastatic cancer from a variety of solid tumors followed by a dose-confirmation phase in pre-specified tumor types. This manuscript reports on 2 of 5 groups. The primary objective was to determine the recommended phase 2 dose of crenigacestat combined with other anticancer agents (gemcitabine/cisplatin or gemcitabine/carboplatin). Secondary objectives included evaluation of safety, tolerability, preliminary efficacy, and pharmacokinetics.
RESULTS
Patients (N = 31) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 6 patients. The recommended phase 2 dose for crenigacestat was 50 mg TIW in Part 1 (combined with gemcitabine/cisplatin) and not established in Part 2 (combined with gemcitabine/carboplatin) due to poor tolerability. Patients had at least one treatment-emergent adverse event (TEAE), and most had Grade ≥ 3 TEAEs. Over 50% of the patients experienced gastrointestinal disorders (Grade ≥ 3). No patient had complete response; 5 patients had a partial response. Disease control rates were 62.5% (Part 1) and 60.0% (Part 2).
CONCLUSION
This study demonstrated that the Notch inhibitor, crenigacestat, combined with different anticancer agents (gemcitabine, cisplatin, and carboplatin) was poorly tolerated and resulted in disappointing clinical activity in patients with advanced or metastatic solid tumors.
CLINICALTRIALS
gov Identification Number: NCT02784795.
背景
Notch 信号通路在发育和组织稳态中起着不可或缺的作用。抑制 Notch 信号通路已被确定为肿瘤治疗的合理靶点。Crenigacestat（LY3039478）是一种有效的 Notch 抑制剂，可降低 Notch 信号及其下游生物学效应。
方法
I6F-MC-JJCD 是一项多中心、非随机、开放标签、1b 期研究，在来自多种实体瘤的晚期或转移性癌症患者中进行了 5 个独立的平行剂量递增，然后在预定的肿瘤类型中进行剂量确认阶段。本文报告了 5 个组中的 2 个。主要目的是确定与其他抗癌药物（吉西他滨/顺铂或吉西他滨/卡铂）联合使用的 crenigacestat 的推荐 2 期剂量。次要目标包括评估安全性、耐受性、初步疗效和药代动力学。
结果
患者（N=31）于 2016 年 11 月至 2019 年 7 月接受治疗。6 例患者出现剂量限制毒性。由于耐受性差，crenigacestat 的推荐 2 期剂量在第 1 部分（与吉西他滨/顺铂联合使用）为 50mgTIW，在第 2 部分（与吉西他滨/卡铂联合使用）尚未确定。患者至少发生一次治疗后出现的不良事件（TEAE），大多数患者发生 3 级或以上的 TEAE。超过 50%的患者出现胃肠道疾病（3 级或以上）。没有患者出现完全缓解，5 例患者出现部分缓解。疾病控制率分别为 62.5%（第 1 部分）和 60.0%（第 2 部分）。
结论
这项研究表明，Notch 抑制剂 crenigacestat 与不同的抗癌药物（吉西他滨、顺铂和卡铂）联合使用耐受性差，导致晚期或转移性实体瘤患者的临床疗效令人失望。
临床试验
gov 标识符：NCT02784795。
Zotero 插件