伊立替康脂质体(ONIVYDE®)联合TAS-102 (LONSURF®)治疗难治性实体瘤的I期研究

IF 2.7 3区 医学 Q2 ONCOLOGY
Investigational New Drugs Pub Date : 2025-06-01 Epub Date: 2025-06-04 DOI:10.1007/s10637-025-01547-2
Nai-Jung Chiang, Li-Yuan Bai, I-Wei Ho, Chih-Hung Hsu, Yi-Hsin Liang, Chang-Fang Chiu, Ching-Chan Lin, Kwang-Yu Chang, Shang-Hung Chen, Hui-Jen Tsai, Yu-Ping Lin, Li-Tzong Chen, Chia-Chi Lin
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引用次数: 0

摘要

Onivyde是一种脂粒包裹的伊立替康,用于晚期胰腺,而TAS-102 (trifluridine/tipiracil)用于转移性结直肠癌和胃癌。本研究旨在确定伊立替康脂质体联合TAS-102的最大耐受剂量(MTD)、推荐II期剂量(RP2D)和安全性。这项多中心I期研究采用3 + 3剂量递增设计。难治性实体恶性肿瘤患者在第1天接受伊立替康50-70 mg/m2的游离基脂质体治疗,在第1-5天接受TAS-102 25-35 mg/m2的治疗,每天两次,14天为一个周期。排除UGT1A1*28 (TA7/TA7)、UGT1A1*6 (A/A)或双杂合(TA6/TA7和G/A)等位基因的患者。允许预防性使用G-CSF。26名可评估的患者被纳入伊立替康(游离基)/TAS-102联合脂体的7个剂量水平:1级(50/ 25mg /m2)、2A级(60/ 25mg /m2)、2B级(50/ 30mg /m2)和3级(60/ 30mg /m2)各3名患者;4A级6个(70/30 mg/m2);4B级3个(60/35 mg/m2);5级(70/35 mg/m2)。另外15名患者在MTD为70/30 mg/m2 (4A级)时被纳入扩展队列,指定为RP2D。43名接受治疗的患者中,总体3-4级治疗相关不良事件发生率为44.2%,其中中性粒细胞减少症(16.3%)、腹泻(14%)和疲劳(11.6%)。18.4%的患者出现部分缓解,主要是神经内分泌肿瘤、胃癌和食管癌。伊立替康脂质体联合TAS-102在RP2D为70/30 mg/m2的情况下,在难治性实体瘤中表现出可接受的安全性和良好的疗效,值得进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A phase I study of liposomal Irinotecan (ONIVYDE®) in combination with TAS-102 (LONSURF®) in refractory solid tumors.

Onivyde, a liposome-encapsulated irinotecan, is used for advanced pancreatic, while TAS-102 (trifluridine/tipiracil) is indicated for metastatic colorectal and gastric cancers. This study aims to determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), and safety profiles of liposomal irinotecan combined with TAS-102. This multicenter, phase I study utilized a 3 + 3 dose-escalation design. Patients with treatment-refractory solid malignancies received free base liposomal irinotecan at 50-70 mg/m2 on Day 1 and TAS-102 at 25-35 mg/m2 twice daily on Days 1-5 of a 14-day cycle. Patients homozygous for UGT1A1*28 (TA7/TA7), UGT1A1*6 (A/A), or double heterozygous (TA6/TA7 and G/A) alleles were excluded. Prophylactic G-CSF was allowed. Twenty-six evaluable patients were enrolled across seven dose levels of liposomal irinotecan (free-base)/TAS-102 combination: 3 patients each at level 1 (50/25 mg/m2), level 2A (60/25 mg/m2), level 2B (50/30 mg/m2), and level 3 (60/30 mg/m2); 6 at level 4A (70/30 mg/m2); 3 at level 4B (60/35 mg/m2); and 5 at level 5 (70/35 mg/m2). An additional 15 patients were enrolled in the expansion cohort at the MTD of 70/30 mg/m2 (level 4A), designated as the RP2D. Overall grade 3-4 treatment-related adverse events occurred in 44.2% of 43 all treated patients, with neutropenia (16.3%), diarrhea (14%), and fatigue (11.6%). Partial responses were observed in 18.4% of patients, predominantly in neuroendocrine tumor, gastric and esophageal carcinomas. The combination of liposomal irinotecan and TAS-102 at the RP2D of 70/30 mg/m2 demonstrated acceptable safety and promising efficacy in refractory solid tumors, warranting further investigation.

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来源期刊
CiteScore
7.60
自引率
0.00%
发文量
121
审稿时长
1 months
期刊介绍: The development of new anticancer agents is one of the most rapidly changing aspects of cancer research. Investigational New Drugs provides a forum for the rapid dissemination of information on new anticancer agents. The papers published are of interest to the medical chemist, toxicologist, pharmacist, pharmacologist, biostatistician and clinical oncologist. Investigational New Drugs provides the fastest possible publication of new discoveries and results for the whole community of scientists developing anticancer agents.
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