一项开放标签研究，旨在确定晚期或转移性实体瘤患者口服ESK-440单药的最大耐受剂量

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia Pub Date : 2025-02-05 DOI:10.1016/j.neo.2025.101133

Russell J. Schilder , Drew Rasco , Manish R. Sharma

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引用次数: 0

摘要

目的间变性淋巴瘤激酶（ALK）失调与多种癌症有关。针对ALK的酪氨酸激酶抑制剂（TKIs）改善了疾病预后，但耐药机制很常见。这项首次人体试验评估了ESK-440，一种ALK和局灶黏附激酶的双重抑制剂，作为对ALK靶向TKIs耐药的癌症的新策略。方法：这项1期开放标签剂量研究评估了ESK-440在晚期或转移性实体瘤患者中的最大耐受剂量（MTD）、安全性、有效性和药代动力学（ClinicalTrials.gov: NCT01922752）。采用3 + 3剂量递增设计，每个28天治疗周期（6 - 8个周期），ESK-440的日剂量范围为25 - 700 mg/天。1b期计划进一步评估ESK-440在MTD的安全性和抗肿瘤活性，但由于申办者的决定而没有进行。结果32名受试者入组，24名（75%）完成第1周期治疗。报告了3例剂量限制性毒性，均为3级恶心(n = 1500mg；N = 2,700 mg)。MTD为每日500毫克。最常见的不良事件（ae）是疲劳和恶心（各占53%）和呕吐（38%）。7名参与者（22%）因ae退出治疗，发生4例死亡，与ESK-440无关。没有参与者有完全或部分反应；7名参与者的最佳总体反应是病情稳定。结论ssk -440安全、耐受，最大耐受剂量为500mg / d；然而，由于赞助商的决定，该研究被提前终止。

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An open-label study to determine the maximum tolerated dose of oral ESK-440 administered as a single agent in patients with advanced or metastatic solid tumors

Purpose

Anaplastic lymphoma kinase (ALK) dysregulation is implicated in numerous cancers. Tyrosine kinase inhibitors (TKIs) targeting ALK have improved disease outcomes, but resistance mechanisms are common. This first-in-human trial evaluates ESK-440, a dual inhibitor of ALK and focal adhesion kinase, as a novel strategy for cancers with resistance to ALK-targeting TKIs.

Methods

This phase 1, open-label, dose-finding study evaluated the maximum tolerated dose (MTD), safety, efficacy, and pharmacokinetics of ESK-440 in participants with advanced or metastatic solid tumors (ClinicalTrials.gov: NCT01922752). A 3 + 3 dose-escalation design, with daily doses ranging from 25 to 700 mg/day of ESK-440 for each 28-day treatment cycle (6 to 8 cycles) was utilized to identify the MTD. A phase 1b was planned to further evaluate ESK-440 safety and antitumor activity at the MTD but was not performed due to sponsor decision.

Results

32 participants were enrolled and 24 (75 %) completed cycle 1 of treatment. Three dose-limiting toxicities, all grade 3 nausea, were reported (n = 1, 500 mg; n = 2, 700 mg). The MTD was determined to be 500 mg daily. The most frequent adverse events (AEs) were fatigue and nausea (53 % each) and vomiting (38 %). Seven participants (22 %) withdrew from treatment due to AEs and 4 deaths occurred, none related to ESK-440. No participant had a complete or partial response; the best overall response was stable disease in 7 participants.

Conclusions

ESK-440 was safe and tolerable with a maximum tolerated dose of 500 mg daily; however, the study was terminated early based on sponsor decision.

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.