Chiang Nai-Jung, Bai Li-Yuan, Ho I-Wei, Hsu Chih-Hung, Liang Yi-Hsin, Chiu Chang-Fang, Lin Ching-Chan, Chang Kwang-Yu, Chen Shang-Hung, Tsai Hui-Jen, Lin Yu-Ping, Chen Li-Tzong, Lin Chia-Chi
Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Invest New Drugs. 2025 Jun 4. doi: 10.1007/s10637-025-01547-2.
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/m on Day 1 and TAS-102 at 25-35 mg/m twice daily on Days 1-5 of a 14-day cycle. Patients homozygous for UGT1A128 (TA7/TA7), UGT1A16 (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/m), level 2A (60/25 mg/m), level 2B (50/30 mg/m), and level 3 (60/30 mg/m); 6 at level 4A (70/30 mg/m); 3 at level 4B (60/35 mg/m); and 5 at level 5 (70/35 mg/m). An additional 15 patients were enrolled in the expansion cohort at the MTD of 70/30 mg/m (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/m demonstrated acceptable safety and promising efficacy in refractory solid tumors, warranting further investigation.
奥尼维德（Onivyde）是一种脂质体包裹的伊立替康，用于晚期胰腺癌，而TAS-102（曲氟尿苷/替匹嘧啶）适用于转移性结直肠癌和胃癌。本研究旨在确定脂质体伊立替康联合TAS-102的最大耐受剂量（MTD）、推荐的II期剂量（RP2D）和安全性。这项多中心I期研究采用了3+3剂量递增设计。治疗难治性实体恶性肿瘤患者在第1天接受50-70mg/m²的游离碱脂质体伊立替康，在14天周期的第1-5天每天两次接受25-35mg/m²的TAS-102。排除UGT1A128（TA7/TA7）、UGT1A16（A/A）或双杂合子（TA6/TA7和G/A）等位基因的纯合子患者。允许使用预防性粒细胞集落刺激因子（G-CSF）。在脂质体伊立替康（游离碱）/TAS-102联合用药的七个剂量水平上共纳入了26例可评估患者：1级（50/25mg/m²）、2A 级（60/25mg/m²）、2B级（50/30mg/m²）和3级（60/30mg/m²）各3例；4A级（70/30mg/m²）6例；4B级（60/35mg/m²）3例；5级（70/35mg/m²）5例。另外15例患者在70/30mg/m²（4A级）的MTD扩展队列中入组，该剂量被指定为RP2D。在43例所有接受治疗的患者中，44.2%发生了3-4级总体治疗相关不良事件，包括中性粒细胞减少（16.3%）、腹泻（14%）和疲劳（11.6%）。18.4%的患者观察到部分缓解，主要见于神经内分泌肿瘤、胃癌和食管癌。脂质体伊立替康与TAS-102以70/30mg/m²的RP2D联合用药在难治性实体肿瘤中显示出可接受的安全性和有前景的疗效，值得进一步研究。
