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GSK-3β抑制剂elraglusib(9-ING-41)联合吉西他滨加纳米白蛋白结合型紫杉醇用于既往未治疗的转移性胰腺癌的II期研究。

Phase II study of elraglusib (9-ING-41), a GSK-3β inhibitor, in combination with gemcitabine plus nab-paclitaxel in previously untreated metastatic pancreatic cancer.

作者信息

Mahalingam D, Saeed A, Powell S F, Huerta M, Sahai V, Coveler A L, Davis E J, Steeghs N, Mulcahy M, Raufi A G, Cavalcante L, Cervantes A, Berlin J, Weisskittel T, Ugolkov A, Mazar A P, Mikrut W, Smith S, Giles F J, Carneiro B A

机构信息

Northwestern University, Chicago, USA.

University of Pittsburgh Medical Center (UPMC) and Hillman Cancer Center, Pittsburgh, USA.

出版信息

ESMO Open. 2025 May 21;10(6):105122. doi: 10.1016/j.esmoop.2025.105122.

Abstract

INTRODUCTION

The purpose of this study was to assess the efficacy and safety of elraglusib (9-ING-41), a GSK-3β inhibitor, in combination with gemcitabine/nab-paclitaxel (GnP) in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).

MATERIAL AND METHODS

In a nonrandomized, Simon's two-stage, phase II study, patients with mPDAC received elraglusib 15 mg/kg on days 1 and 4 each week and GnP on days 1, 8, and 15 in a 28-day cycle. The primary endpoint was disease control rate (DCR); secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-emergent adverse events (TEAEs).

RESULTS

A total of 42 patients, who were enrolled and treated, had a median age of 67 years and were 57.1% male. Overall, 38 patients received elraglusib at 15 mg/kg and 4 at 9.3 mg/kg with GnP. DCR was 35.7% [95% confidence interval (CI) 21.6% to 52.0%], and ORR was 26.2%. The median PFS and OS were 5.4 months (95% CI 4.4-9.2 months) and 11.9 months (95% CI 7.8-16.5 months), respectively. Most common TEAEs were visual impairment (83.3%), fatigue (69%), and nausea (66.7%). Grade ≥3 TEAEs occurred in 85.7% of patients and included neutropenia (52.4%), leukopenia (42.9%), and fatigue (21.4%). The dose of elraglusib was reduced to 9.3 mg/kg due to increased exacerbation of GnP-related toxicities and frequent dose interruptions and reductions of elraglusib.

CONCLUSIONS

Elraglusib/GnP showed preliminary clinical activity. In terms of safety, elraglusib resulted in a modest exacerbation of GnP-related toxicities, leading to a dose reduction of elraglusib to 9.3 mg/kg twice a week. Based on the initial efficacy and safety data, the study was amended to a randomized phase II study that will evaluate the 9.3 mg/kg dose.

摘要

引言

本研究旨在评估糖原合成酶激酶-3β(GSK-3β)抑制剂elraglusib(9-ING-41)联合吉西他滨/纳米白蛋白结合型紫杉醇(GnP)用于既往未接受过治疗的转移性胰腺导管腺癌(mPDAC)的疗效和安全性。

材料与方法

在一项非随机、西蒙两阶段II期研究中,mPDAC患者在每28天为一个周期的第1天和第4天接受15mg/kg的elraglusib治疗,在第1天、第8天和第15天接受GnP治疗。主要终点为疾病控制率(DCR);次要终点为客观缓解率(ORR)、无进展生存期(PFS)、总生存期(OS)以及治疗期间出现的不良事件(TEAE)。

结果

共有42例入组并接受治疗的患者,中位年龄为67岁,男性占57.1%。总体而言,38例患者接受15mg/kg的elraglusib联合GnP治疗,4例接受9.3mg/kg 的elraglusib联合GnP治疗。DCR为35.7%[95%置信区间(CI)21.6%至52.0%],ORR为26.2%。中位PFS和OS分别为5.4个月(95%CI 4.4 - 9.2个月)和11.9个月(95%CI 7.8 - 16.5个月)。最常见的TEAE为视力损害(83.3%)、疲劳(69%)和恶心(66.7%)。≥3级TEAE发生在85.7%的患者中,包括中性粒细胞减少(52.4%)、白细胞减少(42.9%)和疲劳(21.4%)。由于GnP相关毒性加剧以及elraglusib频繁的剂量中断和减少,elraglusib的剂量降至9.3mg/kg。

结论

Elraglusib/GnP显示出初步的临床活性。在安全性方面,elraglusib导致GnP相关毒性略有加剧,使得elraglusib的剂量降至每周两次9.3mg/kg。基于初始疗效和安全性数据,该研究修订为一项随机II期研究,将评估9.3mg/kg的剂量。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c83/12148735/91db9db329cc/gr1.jpg

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