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 kin...
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| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000120 |
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| Summary: | 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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| ISSN: | 1476-5586 |