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Safety and Antitumor Activity of Repeated ASP3026 Administration in Japanese Patients with Solid Tumors: A Phase I
Akira Ono1, Haruyasu Murakami2, Takashi Seto3
1Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan.
Background And Objective:
Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required.
Methods:
This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts.
Results:
Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group).
Conclusion:
ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile.
Clinical Trial Registration:
This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.
Insights
This study evaluated ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. The maximum tolerated dose was 200 mg, showing potential therapeutic benefit with a tolerable safety profile for ALK-rearranged solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Anaplastic lymphoma kinase gene rearrangements (ALKr) are present in a subset of solid tumors.
- ALK inhibitors are crucial for targeting EML4-ALK proteins but face challenges due to drug resistance.
- Novel ALK inhibitors with distinct kinase selectivity are needed to overcome resistance.
Purpose of the Study:
- To evaluate the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor.
- To determine the maximum tolerated dose (MTD) of ASP3026 in Japanese patients with solid tumors.
- To explore the therapeutic potential of ASP3026 in patients with ALK-aberrant solid tumors.
Main Methods:
- Phase I, non-randomized, open-label study involving 29 Japanese patients with solid tumors.
- Dose escalation and expansion cohorts received daily doses of ASP3026 ranging from 25 mg to 325 mg.
- Assessment of DLT, safety, pharmacokinetics, and antitumor responses.
Main Results:
- The maximum tolerated dose (MTD) of ASP3026 was determined to be 200 mg.
- Treatment-emergent adverse events occurred in 100% of patients, with nausea, decreased appetite, and fatigue being most common.
- Two partial responses were observed: one in Ewing sarcoma and one in an ALK-rearranged inflammatory myofibroblastic tumor.
Conclusions:
- ASP3026 at a 200 mg dose demonstrated a tolerable safety profile in Japanese patients with solid tumors.
- The findings suggest that ASP3026 may offer therapeutic benefits for patients with solid tumors, particularly those with ALK alterations.
- Further investigation into ASP3026 as a treatment option for ALK-driven malignancies is warranted.
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