Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study.
Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study.
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DOI：
10.1007/s10637-016-0416-x
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发表时间：
2017-08
影响因子：
3.4
通讯作者：
Yamada Y
中科院分区：
文献类型：
--
作者：
Saka H;Kitagawa C;Kogure Y;Takahashi Y;Fujikawa K;Sagawa T;Iwasa S;Takahashi N;Fukao T;Tchinou C;Landers D;Yamada Y
背景：AZD4547是一种有效的、口服的、高选择性的成纤维细胞生长因子受体(FGFR)抑制剂，临床开发中用于治疗存在一系列FGFR异常的肿瘤，包括FGFR突变、扩增和融合。方法这项开放的I期多中心研究(NCT01213160)评估了AZD4547单一疗法在日本晚期实体肿瘤患者中的安全性、药代动力学和初步抗肿瘤疗效(RECIST V1.1)。A部分是剂量递增部分；B部分是FGFR扩增肿瘤患者的剂量扩大部分，经荧光原位杂交证实。结果A组30例，每日2次，每次40~120 mg；B组4例，每日1次，每次160 mg，每日2次，每次80 mg。没有观察到剂量限制毒性，也没有确定最大耐受量。最常见的不良反应(AEs；任何级别)是：动作障碍(50%)；口腔炎(41%)；腹泻(38%)；高磷血症(38%)；口干(35%)。常见的≥3级不良反应为恶心(12%)和中性粒细胞减少(9%)。未观察到完全或部分反应：A组有21例患者在4周出现稳定的≥，B组有1/4的患者在10周出现稳定的≥，单次和多次给药后吸收速率中等，血药浓度高峰一般出现在给药后3-4小时，然后双相下降，终端半衰期约为30小时，至第8天达到稳定。结论AZD4547在日本患者中耐受性良好，对病情稳定的≥的最佳反应为4周。
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.
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影响因子：
45.3
作者：
Escudier, Bernard;Eisen, Tim;Bukowski, Ronald M.
通讯作者：
Bukowski, Ronald M.
影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D
影响因子：
1.5
作者：
Brown, AP;Courtney, CL;Graziano, MJ
通讯作者：
Graziano, MJ
影响因子：
2.3
作者：
Holzmann K;Grunt T;Heinzle C;Sampl S;Steinhoff H;Reichmann N;Kleiter M;Hauck M;Marian B
通讯作者：
Marian B
DOI：
10.1056/nejmoa1306494
发表时间：
2013-11-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cortes JE;Kim DW;Pinilla-Ibarz J;le Coutre P;Paquette R;Chuah C;Nicolini FE;Apperley JF;Khoury HJ;Talpaz M;DiPersio J;DeAngelo DJ;Abruzzese E;Rea D;Baccarani M;Müller MC;Gambacorti-Passerini C;Wong S;Lustgarten S;Rivera VM;Clackson T;Turner CD;Haluska FG;Guilhot F;Deininger MW;Hochhaus A;Hughes T;Goldman JM;Shah NP;Kantarjian H;PACE Investigators
通讯作者：
PACE Investigators