Department of Internal Oncology, Erasmus Medical Centre Cancer Institute, Dr. Molenwaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute, Plesmanlaan 12, 11066 CX, Amsterdam, The Netherlands.
Target Oncol. 2019 Feb;14(1):43-55. doi: 10.1007/s11523-018-00617-1.
Overexpression/activation of focal adhesion kinase (FAK) in human malignancies has led to its evaluation as a therapeutic target. We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor.
Our objectives were to identify the maximum tolerated dose (MTD), and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker expression, and preliminary activity.
The study comprised a standard 3 + 3 dose-escalation phase followed by an expansion phase in patients with selected advanced, nonhematologic malignancies.
Thirty-three patients received BI 853520 in the dose-escalation phase; the MTD was 200 mg once daily (QD). Dose-limiting toxicities included proteinuria and fatigue, both of which were grade 3. Preliminary PK data supported QD dosing. In the expansion cohort, 63 patients received BI 853520 200 mg QD. Drug-related adverse events (AEs) in > 10% of patients included proteinuria (57%), nausea (57%), fatigue (51%), diarrhea (48%), vomiting (40%), decreased appetite (19%), and peripheral edema (16%). Most AEs were grade 1-2; grade 3 proteinuria, reported in 13 patients (21%), was generally reversible upon treatment interruption. Nineteen patients underwent dose reduction due to AEs, and three drug-related serious AEs were reported, none of which were fatal. Preliminary PD analysis indicated target engagement. Of 63 patients, 49 were evaluable; 17 (27%) achieved a best response of stable disease (4 with 150 + days), and 32 (51%) patients had progressive disease.
BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies. CLINICALTRIALS.
NCT01335269.
在人类恶性肿瘤中，粘着斑激酶（FAK）的过度表达/激活导致其被评估为一种治疗靶点。我们报告了新型、强效、高度选择性的 FAK 抑制剂 BI 853520 的首次人体 I 期研究。
我们的目的是确定最大耐受剂量（MTD），并评估安全性、药代动力学（PK）、药效学（PD）、生物标志物表达和初步疗效。
该研究包括标准的 3+3 剂量递增阶段，随后在选定的晚期非血液恶性肿瘤患者中进行扩展阶段。
33 名患者在剂量递增阶段接受 BI 853520 治疗；MTD 为每日一次 200mg（QD）。剂量限制性毒性包括蛋白尿和疲劳，均为 3 级。初步 PK 数据支持 QD 给药。在扩展队列中，63 名患者接受 BI 853520 200mg QD。药物相关不良事件（AE）发生率超过 10%的患者包括蛋白尿（57%）、恶心（57%）、疲劳（51%）、腹泻（48%）、呕吐（40%）、食欲下降（19%）和外周水肿（16%）。大多数 AE 为 1-2 级；13 名患者（21%）报告了 3 级蛋白尿，在中断治疗后通常是可逆的。19 名患者因 AE 而减少剂量，报告了 3 例与药物相关的严重 AE，均非致命。初步 PD 分析表明存在靶标结合。在 63 名可评估患者中，有 49 名患者达到最佳反应，其中 17 名（27%）患者疾病稳定（4 名患者稳定期超过 150 天），32 名（51%）患者疾病进展。
在选定的晚期非血液恶性肿瘤患者中，BI 853520 以 200mg QD 的 MTD 给药，具有可管理和可接受的安全性、良好的 PK 特征和适度的抗肿瘤活性。临床试验。
gov 标识符：NCT01335269。
