National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
The Cancer Institute Hospital of Japanese Foundation of Cancer Research, Tokyo, Japan.
Invest New Drugs. 2018 Jun;36(3):424-434. doi: 10.1007/s10637-017-0514-4. Epub 2017 Sep 30.
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.
NCT01962532.
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。
