British Columbia Cancer, 600 West 10th Ave, Vancouver, BC, V5Z 4E6, Canada.
Duke University Medical Center, Durham, NC, USA.
Target Oncol. 2023 Jan;18(1):105-118. doi: 10.1007/s11523-022-00931-9. Epub 2022 Dec 2.
Heightened signaling by mesenchymal epithelial transition factor (MET) is implicated in tumorigenesis. Glesatinib is an investigational, oral inhibitor of MET and AXL.
This phase I study determined the maximum tolerated dose (MTD), recommended phase II dose (RP2D), and safety profile of glesatinib in patients with advanced or unresectable solid tumors. Antitumor activity and pharmacokinetics (PK) were secondary objectives.
Four formulations of glesatinib glycolate salt (capsule, unmicronized, micronized, and micronized version 2 [V2] tablets) and two free-base formulations (free-base suspension [FBS] capsule and spray-dried dispersion [SDD] tablet), developed to enhance drug exposure and optimize manufacturing processes, were evaluated in patients with genetically unselected advanced/unresectable solid tumors. MTD, based on dose-limiting toxicities (DLTs) observed during the first 21-day treatment cycle, was further evaluated in dose-expansion cohorts comprising patients with overexpression of MET and/or AXL, MET/AXL amplification, MET-activating mutations, or MET/AXL rearrangements for confirmation as the RP2D.
Glesatinib was evaluated across 27 dose-escalation cohorts (n = 108). Due to suboptimal exposure with glesatinib glycolate salt formulations in the initial cohorts, investigations subsequently focused on the FBS capsule and SDD tablet; for these formulations, MTD was identified as 1050 mg twice daily and 750 mg twice daily, respectively. An additional 71 patients received glesatinib in the FBS and SDD dose-expansion cohorts. At MTDs, the most frequent treatment-related adverse events were diarrhea (FBS, 83.3%; SDD, 75.0%), nausea (57.1%, 30.6%), vomiting (45.2%, 25.0%), increased alanine aminotransferase (45.2%, 30.6%), and increased aspartate aminotransferase (47.6%, 27.8%). Exploratory pharmacodynamic analyses indicated target engagement and inhibition of MET by glesatinib. Antitumor activity was observed with glesatinib FBS 1050 mg twice daily and SDD 750 mg twice daily in tumors harboring MET/AXL alteration or aberrant protein expression, particularly in patients with non--small cell lung cancer (NSCLC). In patients with NSCLC, the objective response rate was 25.9% in those with MET/AXL mutation or amplification and 30.0% in a subset with MET-activating mutations. All six partial responses occurred in patients with tumors carrying MET exon 14 deletion mutations.
The safety profile of single-agent glesatinib was acceptable. SDD 750 mg twice daily was selected as the preferred glesatinib formulation and dose based on clinical activity, safety, and PK data. Observations from this study led to initiation of a phase II study of glesatinib in patients with NSCLC stratified by type of MET alteration (NCT02544633).
ClinicalTrials.gov NCT00697632; June 2008.
间质上皮转化因子（MET）的信号增强与肿瘤发生有关。Glesatinib 是一种研究性的、口服的 MET 和 AXL 抑制剂。
本Ⅰ期研究旨在确定晚期或不可切除的实体瘤患者中 glesatinib 的最大耐受剂量（MTD）、推荐的Ⅱ期剂量（RP2D）和安全性特征。抗肿瘤活性和药代动力学（PK）是次要目标。
评估了 4 种 glesatinib 草酸盐盐（胶囊、非微粉化、微粉化和微粉化版本 2 [V2]片剂）和 2 种游离碱制剂（游离碱混悬液[FBS]胶囊和喷雾干燥分散体[SDD]片剂），这些制剂旨在提高药物暴露量并优化制造工艺，用于治疗遗传上未选择的晚期/不可切除的实体瘤患者。根据第一个 21 天治疗周期中观察到的剂量限制毒性（DLTs）进一步评估 MTD，并在包含 MET 和/或 AXL 过表达、MET/AXL 扩增、MET 激活突变或 MET/AXL 重排的患者的剂量扩展队列中进行确认，以确定 RP2D。
glesatinib 在 27 个剂量递增队列（n=108）中进行了评估。由于在最初的队列中 glesatinib 草酸盐盐制剂的暴露量不理想，随后的研究集中在 FBS 胶囊和 SDD 片剂上；对于这些制剂，确定 MTD 分别为 1050mg 每日 2 次和 750mg 每日 2 次。另外 71 名患者在 FBS 和 SDD 剂量扩展队列中接受了 glesatinib 治疗。在 MTD 时，最常见的治疗相关不良事件是腹泻（FBS，83.3%；SDD，75.0%）、恶心（57.1%，30.6%）、呕吐（45.2%，25.0%）、丙氨酸氨基转移酶升高（45.2%，30.6%）和天冬氨酸氨基转移酶升高（47.6%，27.8%）。探索性药效动力学分析表明 glesatinib 可靶向结合并抑制 MET。在携带 MET/AXL 改变或异常蛋白表达的肿瘤中，FBS 1050mg 每日 2 次和 SDD 750mg 每日 2 次的 glesatinib 观察到抗肿瘤活性，特别是在非小细胞肺癌（NSCLC）患者中。在 NSCLC 患者中，MET/AXL 突变或扩增患者的客观缓解率为 25.9%，具有 MET 激活突变的亚组患者的客观缓解率为 30.0%。所有 6 例部分缓解均发生在携带 MET 外显子 14 缺失突变的肿瘤患者中。
单药 glesatinib 的安全性特征可接受。基于临床活性、安全性和 PK 数据，选择 SDD 750mg 每日 2 次作为首选的 glesatinib 制剂和剂量。本研究的观察结果导致启动了一项在非小细胞肺癌患者中按 MET 改变类型分层的 glesatinib Ⅱ期研究（NCT02544633）。
ClinicalTrials.gov NCT00697632；2008 年 6 月。
