Document Type
Article
Publication Date
2-5-2025
Abstract
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 500mg daily; however, the study was terminated early based on sponsor decision.
Recommended Citation
Schilder, Russell J.; Rasco, Drew; and Sharma, Manish R., "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" (2025). Kimmel Cancer Center Faculty Papers. Paper 144.
https://jdc.jefferson.edu/kimmelccfp/144
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
39914170
Language
English
Comments
This article is the author's final published version in Neoplasia (United States), Volume 61, 2025, Article number 101133.
The published version is available at https://doi.org/10.1016/j.neo.2025.101133.
Copyright © 2025 Published by Elsevier Inc