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Updated: May 6, 2026

Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
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An open-label study to determine the maximum tolerated dose of oral ESK-440 administered as a single agent in

Russell J Schilder1, Drew Rasco2, Manish R Sharma3

  • 1Gynecologic Medical Oncology, Early Drug Development Unit, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th St, Philadelphia, PA, USA.

Neoplasia (New York, N.Y.)
|February 6, 2025
PubMed
Abstract

Insights

This study found that ESK-440, a dual ALK and focal adhesion kinase inhibitor, is safe and tolerable up to 500mg daily for advanced cancers. However, the trial was stopped early, showing no complete or partial responses but stable disease in some patients.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • Anaplastic lymphoma kinase (ALK) dysregulation drives various cancers, with tyrosine kinase inhibitors (TKIs) offering improved outcomes.
  • Resistance to ALK-targeting TKIs is a significant clinical challenge, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To evaluate the safety, tolerability, and efficacy of ESK-440, a novel dual inhibitor of ALK and focal adhesion kinase.
  • To determine the maximum tolerated dose (MTD) of ESK-440 in patients with advanced or metastatic solid tumors resistant to ALK-targeting TKIs.

Main Methods:

  • A phase 1, open-label, dose-escalation study (3+3 design) was conducted.
  • Participants received daily doses of ESK-440 ranging from 25 to 700 mg over 28-day cycles.
  • The study aimed to identify the MTD and assess safety, pharmacokinetics, and preliminary efficacy.

Main Results:

  • 32 participants were enrolled; 24 completed cycle 1. The MTD was established at 500 mg daily.
  • Common adverse events included fatigue and nausea (53% each). Three dose-limiting toxicities (Grade 3 nausea) occurred at higher doses.
  • No complete or partial responses were observed; stable disease was the best overall response in 7 participants (22%).

Conclusions:

  • ESK-440 demonstrated a safe and tolerable profile with an MTD of 500 mg daily.
  • Despite early termination due to sponsor decision, the study provides initial safety and tolerability data for this novel dual inhibitor.
  • Further investigation may be warranted to explore its potential in specific resistant cancer populations.
Keywords:
Anaplastic lymphoma kinase (ALK)ESK-440Focal adhesion kinase (FAK)Solid tumorsTyrosine kinase inhibitor (TKI)

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