Sarah Cannon Research Institute, Nashville, TN, USA.
J Clin Oncol. 2012 May 1;30(13):1527-33. doi: 10.1200/JCO.2011.38.9346. Epub 2012 Mar 26.
PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271.
Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients.
Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration-time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles.
The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.
PF-00562271 是一种新型的粘着斑激酶（FAK）抑制剂。本研究的目的是确定推荐的 II 期剂量（RP2D），并评估 PF-00562271 的安全性、耐受性、药代动力学（PK）、药效学（PD）和抗肿瘤活性。
第 1 部分为无食物和有食物的剂量递增。第 2 部分在 RP2D 下招募特定肿瘤类型进行扩展，并评估 PF-00562271 对亚组患者单剂量咪达唑仑 PK 的影响。
99 名患者（中位年龄 60 岁；98%的东部肿瘤协作组表现状态为 0 或 1）接受了 12 个空腹和 3 个进食队列的治疗。125mg 每日两次的进食剂量被认为是最大耐受剂量（MTD）和 RP2D。3 级剂量限制性毒性包括头痛、恶心/呕吐、脱水和水肿。恶心是最常见的毒性（60%的患者，所有等级 1 或 2 在 RP2D）。PF-00562271 的暴露随剂量增加而增加；血清浓度-时间曲线显示出特征性的非线性分布。稳态暴露在 1 周内达到。在合并用药时，咪达唑仑最大观察到的血清浓度和血清浓度-时间曲线下面积的几何均数分别增加了 60%和两倍多。在扩展队列中，14 名可通过 [(18)F]氟脱氧葡萄糖正电子发射断层扫描评估的患者中，观察到 7 个代谢反应。在常规影像学检查中，31 名患者在首次复查扫描时病情稳定，其中 15 名患者在 6 个或更多周期内保持稳定。
PF-00562271 的 MTD 和 RP2D 是每天两次进食 125mg。PF-00562271 表现出时间和剂量依赖性的非线性 PK，可能是一种有效的 CYP3A 抑制剂。这项首次人体研究支持进一步研究 FAK 作为一个有前途的治疗靶点。
