A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors

被引：29

作者：

Azaro, Analia ^{[1
,2
]}

Massard, Christophe ^{[3
]}

Tap, William D. ^{[4
,5
]}

Cassier, Philippe A. ^{[6
]}

Merchan, Jaime ^{[7
]}

Italiano, Antoine ^{[8
]}

Anderson, Bailey ^{[9
]}

Yuen, Eunice ^{[9
]}

Yu, Danni ^{[9
]}

Oakley, Gerard, III ^{[9
]}

Benhadji, Karim A. ^{[10
]}

Pant, Shubham ^{[11
]}

机构：

[1] Vall dHebron Univ Hosp, Dept Med Oncol, Mol Therapeut Res Unit, Barcelona, Spain

[2] Univ Autonoma Barcelona UAB, Dept Pharmacol, Barcelona, Spain

[3] Univ Paris Sud, Univ Paris Saclay, Drug Dev Dept DITEP, Gustave Roussy,INSERM,Unit U981, Villejuif, France

[4] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[5] Weill Cornell Med Coll, 1275 York Ave, New York, NY 10021 USA

[6] Ctr Leon Berard, Dept Med Oncol, Lyon, France

[7] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[8] Inst Bergonie, Bordeaux, France

[9] Eli Lilly & Co, Indianapolis, IN 46285 USA

[10] Eli Lilly & Co, New York, NY USA

[11] Univ Texas MD Anderson Canc Ctr, Univ Texas Med Ctr, Dept Invest Canc Therapeut, Div Canc Med, Houston, TX 77030 USA

来源：

INVESTIGATIONAL NEW DRUGS | 2021年 / 39卷 / 04期

关键词：

LY3039478; Crenigacestat; Notch inhibition; Phase; 1; Metastatic cancer; Abemaciclib; CANCER; HEDGEHOG; WNT; PATHWAYS;

D O I：

10.1007/s10637-021-01094-6

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1089 / 1098

页数：10

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