A phase 1 study of oral ASP5878, a selective small-molecule inhibitor of fibroblast growth factor receptors 1–4, as a single dose and multiple doses in patients with solid malignancies

被引:0
作者
Noboru Yamamoto
Baek-Yeol Ryoo
Bhumsuk Keam
Masatoshi Kudo
Chia-Chi Lin
Futoshi Kunieda
Howard A. Ball
Diarmuid Moran
Kanji Komatsu
Kentaro Takeda
Musashi Fukuda
Junji Furuse
Satoshi Morita
Toshihiko Doi
机构
[1] National Cancer Center Hospital,Department of Experimental Therapeutics, Department of Thoracic Oncology
[2] Asan Medical Center,Department of Oncology
[3] University of Ulsan,Department of Internal Medicine
[4] Seoul National University Hospital,Department of Gastroenterology and Hepatology
[5] School of Medicine,Department of Oncology
[6] Kindai University,Medical Science Oncology
[7] National Taiwan University Hospital,Clinical Pharmacology & Exploratory Development – Oncology
[8] Astellas Pharma Global Development,Clinical Pharmacology
[9] Inc.,Data Science
[10] Astellas Pharma Global Development,Japan
[11] Inc.,Asia Data Science
[12] Astellas Pharma,Department of Medical Oncology
[13] Inc.,Department of Biomedical Statistics and Bioinformatics
[14] Astellas Pharma Global Development,Experimental Therapeutics of Digestive Endoscopy/Gastrointestinal Oncology
[15] Inc.,undefined
[16] Astellas Pharma,undefined
[17] Inc.,undefined
[18] Kyorin University School of Medicine,undefined
[19] Faculty of Medicine,undefined
[20] Graduate School of Medicine,undefined
[21] Kyoto University,undefined
[22] National Cancer Center Hospital East,undefined
来源
Investigational New Drugs | 2020年 / 38卷
关键词
Fibroblast growth factor receptor; Inhibitor; ASP5878; Dose-expansion; Phase 1; First-in-human;
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摘要
ASP5878 is a selective small-molecule inhibitor of fibroblast growth factor receptors (FGFRs). This study investigated safety, tolerability, and antitumor effect of single and multiple oral doses of ASP5878 in patients with solid tumors. This phase 1, open label, first-in-human study comprised dose-escalation and dose-expansion parts. Primary objectives of the dose-escalation part were to identify the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended dose of ASP5878 for the dose-expansion part. Nine dose cohorts of ASP5878 were evaluated (0.5─2 mg once daily; 2─40 mg twice daily [BID]). A single dose of ASP5878 was followed by a 2-day pharmacokinetic collection, and then either 28-day cycles of daily dosing (ASP5878 ≤ 10 mg BID) or 5-day dosing/2-day interruption (ASP5878 ≥ 20 mg BID). The primary objective of the dose-expansion part was to determine the safety of ASP5878 (16 mg BID) administered in 28-day cycles of 5-day dosing/2-day interruption in patients with urothelial carcinoma, hepatocellular carcinoma, or squamous cell lung carcinoma with FGFR genetic alterations. Safety was assessed by monitoring adverse events (AEs). Thirty-five patients were enrolled and 31 discontinued in the dose-escalation part; 51 patients were enrolled and 51 discontinued in the dose-expansion part. In the dose-escalation part, 66.7% of patients in the 20 mg BID 5-day dosing/2-day interruption group reported DLTs of hyperphosphatemia. The recommended dose for the dose-expansion part was 16 mg BID. Common AEs included retinal detachment, diarrhea, and increased alanine aminotransferase. One death occurred that was not related to ASP5878. ASP5878 was well tolerated with manageable toxicities including hyperphosphatemia.
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页码:445 / 456
页数:11
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