Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
Department of Pharmacology, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
Invest New Drugs. 2021 Aug;39(4):1089-1098. doi: 10.1007/s10637-021-01094-6. Epub 2021 Mar 8.
Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. 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 prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0-82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.
Notch 信号通路在发育和组织稳态中发挥着重要作用。 Notch 信号通路的失调与多种恶性肿瘤有关。 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。 I6F-MC-JJCD 是一项多中心、非随机、开放性、1b 期研究，共纳入来自多种实体瘤的晚期或转移性癌症患者 5 组，每组分别进行 5 个平行剂量递增，随后在预定肿瘤类型中进行剂量确认阶段。本文报告了 5 组中的 3 组。主要目的是确定 crenigacestat 联合其他抗癌药物（taladegib、LY3023414[磷酸肌醇 3-激酶双重抑制剂；雷帕霉素的作用靶点]或 abemaciclib）的推荐 2 期剂量。次要目标包括评估安全性、耐受性、疗效和药代动力学。患者（N=63）于 2016 年 11 月至 2019 年 7 月接受治疗。12 例患者出现剂量限制性毒性，主要为胃肠道（腹泻、恶心、呕吐）。crenigacestat 的最大耐受剂量在 B 部分（LY3023414）为 25mg，在 C 部分（abemaciclib）为 50mg，在 A 部分（taladegib）由于毒性未确定。患者至少有 1 例不良事件（AE），75.0-82.6%为≥3 级全因 AE。没有患者出现完全或部分缓解。疾病控制率分别为 18.8%（B 部分）和 26.1%（C 部分）。在确认剂量队列触发之前，该研究已终止。这项研究表明，crenigacestat 联合不同的抗癌药物（taladegib、LY3023414 或 abemaciclib）耐受性差，导致剂量降低，晚期或转移性实体瘤患者的临床活性令人失望。NCT02784795 登记日期：2016 年 5 月 27 日。
