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在晚期或难治性实体瘤患者中,泛成纤维细胞生长因子受体(FGFR)酪氨酸激酶抑制剂erdafitinib 的安全性、药代动力学和药效学。

Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors.

机构信息

National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.

The Cancer Institute Hospital of Japanese Foundation of Cancer Research, Tokyo, Japan.

出版信息

Invest New Drugs. 2018 Jun;36(3):424-434. doi: 10.1007/s10637-017-0514-4. Epub 2017 Sep 30.

Abstract

UNLABELLED

Introduction This phase 1, open-label, multicenter, single-arm, dose-escalation study aimed to evaluate safety, pharmacokinetics (PK), and pharmacodynamics of erdafitinib (JNJ-42756493), an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, and to determine the recommended phase 2 dose in Japanese patients with advanced or refractory solid tumors. Methods Three to 6 patients were enrolled into sequentially escalating dose cohorts (erdafitinib 2, 4, or 6 mg) with a daily dosing schedule of 21-day cycles or a 7 days-on/7 days-off intermittent schedule (erdafitinib 10 mg or 12 mg) of 28-day cycles. Results Nineteen patients received escalating doses of erdafitinib with a daily or intermittent schedule. The most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (73.7%), nausea (36.8%), stomatitis (26.3%), dysgeusia (26.3%) and dry mouth (21.1%). The maximum tolerated dose was not reached in this study. No Grade 3 or higher TEAEs, or serious TEAEs were noted and no clinically significant changes in vital signs, laboratory parameters, and electrocardiogram readings were observed. However, one case of dose-limiting toxicity in the 12 mg intermittent dosing group was observed: Grade 2 detachment of retinal pigment epithelium (bilateral) with treatment discontinuation. The maximum plasma concentrations of erdafitinib exhibited a dose-dependent increase. The median t ranged from 2 to 3 h after the initial dose to 2-6 h following multiple daily dosing. Based on the safety and PK data, the 10 mg 7 days-on/7 days-off regimen was determined as the recommended phase 2 dose in this study. Conclusions Erdafitinib was well tolerated in Japanese patients with advanced or refractory solid tumors.

TRIAL REGISTRATION

NCT01962532.

摘要

未注明

目的 这项 1 期、开放标签、多中心、单臂、剂量递增研究旨在评估 erdafitinib(JNJ-42756493)在晚期或难治性实体瘤日本患者中的安全性、药代动力学(PK)和药效学,erdafitinib 是一种口服选择性成纤维细胞生长因子受体(FGFR)酪氨酸激酶抑制剂,并确定其在日本患者中的推荐 2 期剂量。方法 3 至 6 名患者按顺序递增剂量队列(erdafitinib 2、4 或 6mg),每日剂量方案为 21 天周期或 7 天/7 天间隔方案(erdafitinib 10mg 或 12mg)28 天周期。结果 19 名患者接受了每日或间歇性方案递增剂量的 erdafitinib 治疗。最常见的治疗相关不良事件(TEAEs)是高磷血症(73.7%)、恶心(36.8%)、口腔炎(26.3%)、味觉障碍(26.3%)和口干(21.1%)。在这项研究中,未达到最大耐受剂量。未观察到 3 级或更高级别的 TEAEs 或严重 TEAEs,也未观察到生命体征、实验室参数和心电图读数的临床意义上的变化。然而,在 12mg 间歇性给药组观察到 1 例剂量限制毒性:双侧视网膜色素上皮脱离(2 级),停药。erdafitinib 的最大血浆浓度呈剂量依赖性增加。中位 t 从初始剂量后 2 至 3 小时到多次每日给药后 2 至 6 小时不等。基于安全性和 PK 数据,确定 10mg 7 天/7 天间隔方案为该研究的推荐 2 期剂量。结论 erdafitinib 在晚期或难治性实体瘤的日本患者中具有良好的耐受性。试验注册:NCT01962532。

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