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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Elsevier
2025-03-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000120 |
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| author | Russell J. Schilder Drew Rasco Manish R. Sharma |
| author_facet | Russell J. Schilder Drew Rasco Manish R. Sharma |
| author_sort | Russell J. Schilder |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-329b7d8decd04731bdb5c059efc7b265 |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-329b7d8decd04731bdb5c059efc7b2652025-02-07T04:47:19ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-03-0161101133An 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 tumorsRussell J. Schilder0Drew Rasco1Manish R. Sharma2Gynecologic Medical Oncology, Early Drug Development Unit, Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th St, Philadelphia, PA, USASTART Center for Cancer Research, 4383 Medical Dr # 3046, San Antonio, TX, USAAffiliation at time of study: University of Chicago, Chicago, IL, USA; START Center for Cancer Research - Midwest (START Midwest), 5800 Foremost Dr SE Suite 100, Grand Rapids, MI, USA; Corresponding author at: Co-Director of Clinical Research, START Midwest, 5800 Foremost Drive SE, Suite 100, Grand Rapids, MI 49546, USA.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.http://www.sciencedirect.com/science/article/pii/S1476558625000120Anaplastic lymphoma kinase (ALK)Focal adhesion kinase (FAK)Solid tumorsESK-440Tyrosine kinase inhibitor (TKI) |
| spellingShingle | Russell J. Schilder Drew Rasco Manish R. Sharma 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 Neoplasia: An International Journal for Oncology Research Anaplastic lymphoma kinase (ALK) Focal adhesion kinase (FAK) Solid tumors ESK-440 Tyrosine kinase inhibitor (TKI) |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Anaplastic lymphoma kinase (ALK) Focal adhesion kinase (FAK) Solid tumors ESK-440 Tyrosine kinase inhibitor (TKI) |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000120 |
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