title: Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study.
abstract: Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization. Results Thirty patients enrolled in Part A (dose range: 40 mg twice daily [bid] to 120 mg bid; 160 mg once daily [qd]), four in Part B (80 mg bid). No dose-limiting toxicities were observed and maximum tolerated dose was not determined. Most common adverse events (AEs; any grade) were: dysgeusia (50% of patients); stomatitis (41%); diarrhoea (38%); hyperphosphataemia (38%); dry mouth (35%). Common grade ≥3 AEs were nausea (12% of patients) and neutropenia (9%). No complete or partial responses were observed: 21/30 patients had stable disease ≥4 weeks in Part A, and 1/4 patients had stable disease ≥10 weeks in Part B. Following single and multiple dosing, absorption rate appeared moderate; peak plasma concentrations generally occurred 3-4 h post-dose, then declined biphasically with terminal half-life ~30 h. Steady state was reached by day 8. Compared with single dosing, plasma concentrations were, on average, 2.4- and 3.3- to 5.4-fold higher after qd and bid dosing, respectively. Conclusions AZD4547 was well tolerated in Japanese patients, with best response of stable disease ≥4 weeks.
authors.affiliation: Department of Medical Oncology, Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi, 460-0001, Japan. saka@med.nagoya-u.ac.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Saka
authors.affiliation: Department of Medical Oncology, Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi, 460-0001, Japan.
authors.forename: Chiyoe
authors.initials: C
authors.lastname: Kitagawa
authors.affiliation: Department of Medical Oncology, Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi, 460-0001, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kogure
authors.affiliation: Department of Gastroenterological Medicine, Hokkaido Cancer Center, Hokkaido, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Gastroenterological Medicine, Hokkaido Cancer Center, Hokkaido, Japan.
authors.forename: Koshi
authors.initials: K
authors.lastname: Fujikawa
authors.affiliation: Department of Gastroenterological Medicine, Hokkaido Cancer Center, Hokkaido, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sagawa
authors.affiliation: Department of Medical Oncology, Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwasa
authors.affiliation: Department of Medical Oncology, Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: R&D, AstraZeneca KK, Osaka, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Fukao
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Tchinou
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Dónal
authors.initials: D
authors.lastname: Landers
authors.affiliation: Department of Medical Oncology, Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D001549:Benzamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011720:Pyrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles; D017468:Receptors, Fibroblast Growth Factor
keywords: AZD4547; FGFR; Japanese; Pharmacokinetics; Phase I; Safety