PMID- 31041575 OWN - NLM STAT- MEDLINE DCOM- 20210303 LR - 20211204 IS - 1573-0646 (Electronic) IS - 0167-6997 (Linking) VI - 38 IP - 2 DP - 2020 Apr TI - 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. PG - 445-456 LID - 10.1007/s10637-019-00780-w [doi] AB - 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 horizontal line 2 mg once daily; 2 horizontal line 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 /= 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. FAU - Yamamoto, Noboru AU - Yamamoto N AD - Department of Experimental Therapeutics, Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. nbryamam@ncc.go.jp. FAU - Ryoo, Baek-Yeol AU - Ryoo BY AD - Department of Oncology, Asan Medical Center, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea. FAU - Keam, Bhumsuk AU - Keam B AD - Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro Jongno-gu, Seoul, 03080, Republic of Korea. FAU - Kudo, Masatoshi AU - Kudo M AD - Department of Gastroenterology and Hepatology, School of Medicine, Kindai University, 3-4-1 Kowakae, Higashiosaka City, Osaka, 577-8502, Japan. FAU - Lin, Chia-Chi AU - Lin CC AD - Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S Rd, Taipei, 10002, Taiwan. FAU - Kunieda, Futoshi AU - Kunieda F AD - Medical Science Oncology, Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA. FAU - Ball, Howard A AU - Ball HA AD - Clinical Pharmacology & Exploratory Development - Oncology, Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA. FAU - Moran, Diarmuid AU - Moran D AD - Clinical Pharmacology & Exploratory Development - Oncology, Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA. FAU - Komatsu, Kanji AU - Komatsu K AD - Clinical Pharmacology, Astellas Pharma, Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan. FAU - Takeda, Kentaro AU - Takeda K AD - Data Science, Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA. FAU - Fukuda, Musashi AU - Fukuda M AD - Japan-Asia Data Science, Astellas Pharma, Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan. FAU - Furuse, Junji AU - Furuse J AD - Department of Medical Oncology, Kyorin University School of Medicine, Faculty of Medicine, 6-20-2, Shinkawa, Mitaka, Tokyo, 181-8611, Japan. FAU - Morita, Satoshi AU - Morita S AD - Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, sakyo-ku, Kyoto, 606-8501, Japan. FAU - Doi, Toshihiko AU - Doi T AD - Experimental Therapeutics of Digestive Endoscopy/Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190430 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (ASP5878) RN - 0 (Antineoplastic Agents) RN - 0 (Parathyroid Hormone) RN - 0 (Phosphates) RN - 0 (Pyrazoles) RN - 0 (Pyrimidines) RN - 0 (Receptors, Fibroblast Growth Factor) RN - 62031-54-3 (Fibroblast Growth Factors) RN - 7Q7P4S7RRE (Fibroblast Growth Factor-23) SB - IM MH - Administration, Oral MH - Adult MH - Aged MH - Antineoplastic Agents/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Carcinoma, Hepatocellular/*drug therapy/metabolism MH - Female MH - Fibroblast Growth Factor-23 MH - Fibroblast Growth Factors/blood MH - Humans MH - Liver Neoplasms/*drug therapy/metabolism MH - Lung Neoplasms/*drug therapy/metabolism MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasms, Squamous Cell/*drug therapy/metabolism MH - Parathyroid Hormone/blood MH - Phosphates/blood MH - Pyrazoles/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Pyrimidines/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Receptors, Fibroblast Growth Factor/*antagonists & inhibitors MH - Treatment Outcome MH - Urologic Neoplasms/*drug therapy/metabolism MH - Young Adult OTO - NOTNLM OT - ASP5878 OT - Dose-expansion OT - Fibroblast growth factor receptor OT - First-in-human OT - Inhibitor OT - Phase 1 EDAT- 2019/05/02 06:00 MHDA- 2021/03/04 06:00 CRDT- 2019/05/02 06:00 PHST- 2019/03/05 00:00 [received] PHST- 2019/04/09 00:00 [accepted] PHST- 2019/05/02 06:00 [pubmed] PHST- 2021/03/04 06:00 [medline] PHST- 2019/05/02 06:00 [entrez] AID - 10.1007/s10637-019-00780-w [pii] AID - 10.1007/s10637-019-00780-w [doi] PST - ppublish SO - Invest New Drugs. 2020 Apr;38(2):445-456. doi: 10.1007/s10637-019-00780-w. Epub 2019 Apr 30.