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

• Published in: Investigational new drugs Vol. 38; no. 2; pp. 445 - 456
• Main Authors: Yamamoto, Noboru, Ryoo, Baek-Yeol, Keam, Bhumsuk, Kudo, Masatoshi, Lin, Chia-Chi, Kunieda, Futoshi, Ball, Howard A., Moran, Diarmuid, Komatsu, Kanji, Takeda, Kentaro, Fukuda, Musashi, Furuse, Junji, Morita, Satoshi, Doi, Toshihiko
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2020; Springer Nature B.V
• Subjects: Administration, Oral; Adult; Aged; Alanine; Alanine transaminase; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Antitumor activity; Bladder cancer; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Diarrhea; Dosage; Expansion; Female; Fibroblast growth factor receptors; Fibroblast Growth Factors - blood; Fibroblasts; Growth factor receptors; Growth factors; Hepatocellular carcinoma; Humans; Hyperphosphatemia; Inhibitors; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Lung carcinoma; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Neoplasms, Squamous Cell - drug therapy; Neoplasms, Squamous Cell - metabolism; Oncology; Parathyroid Hormone - blood; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Phosphates - blood; Pyrazoles - administration & dosage; Pyrazoles - adverse effects; Pyrazoles - blood; Pyrazoles - pharmacokinetics; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Receptors; Receptors, Fibroblast Growth Factor - antagonists & inhibitors; Retina; Safety; Solid tumors; Studies; Toxicity; Treatment Outcome; Urologic Neoplasms - drug therapy; Urologic Neoplasms - metabolism; Urothelial carcinoma; Young Adult; Inhibitor; Phase 1; ASP5878; Dose-expansion; Fibroblast growth factor receptor; First-in-human
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-019-00780-w

Summary 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.