Safety and Antitumor Activity of Repeated ASP3026 Administration in Japanese Patients with Solid Tumors: A Phase I Study

• DOI: 10.1007/s40268-020-00331-2
• Publication Date: 2020-12-17T15:03:54Z
• Authors: Akira Ono; Haruyasu Murakami; Takashi Seto; Toshio Shimizu; Sawori Watanabe; Shigeru Takeshita; Kentaro Takeda; Junko Toyoshima; Itsuro Nagase; Erkut Bahceci; Maiko Morishita; Satoshi Morita; Masahiro Fukuoka; Kazuhiko Nakagawa
• Keywords: Adult; Male; Maximum Tolerated Dose; Administration, Oral; Appetite; Antineoplastic Agents; Sarcoma, Ewing; Drug Administration Schedule; 03 medical and health sciences; 0302 clinical medicine; Asian People; Neoplasms; Humans; Anaplastic Lymphoma Kinase; Original Research Article; Protein Kinase Inhibitors; Fatigue; Aged; Dose-Response Relationship, Drug; Myositis; Nausea; Middle Aged; 3. Good health; Female

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.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.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).ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile.This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.