Dataset from A Phase I Open-Label Dose Escalation Study of the Focal Adhesion Kinase Inhibitor, GSK2256098, in Subjects With Solid Tumors

This study is a Phase I dose escalation study in subjects with solid tumors. Part 1 will identify the maximum tolerated dose (MTD) using a dose-escalation procedure. Following identification of the MTD, enrollment into Parts 2, 3, 4 and 5 may be concurrent. Part 2 will explore further the safety, PK, tolerability, and anti-tumor activity of GSK2256098 in subjects with tumors known to overexpress focal adhesion kinase (FAK). Part 3 will characterize the range of biologically effective doses by assessing pharmacodynamic (PD) markers in hair, skin and tumor tissue at doses that will not go lower than 80 mg or above the MTD dose levels tested during the Phase 1 dose escalation. Part 4 will explore further the safety, PK, tolerability and anti-tumor activity of GSK2256098 in subjects with relapsed glioblastoma multiforme (GBM). The primary objective of this study is to determine the safety, tolerability, and MTD of GSK2256098. Secondary objectives are to characterize the pharmacokinetics (PK) of GSK2256098; to identify a range of biologically active doses; to explore the anti-tumor activity of GSK2256098, and to explore relationships between GSK2256098 PK, PD and clinical endpoints. Part 5 will investigate the time course, the extent of an apparent change in the PK of GSK2256098 following repeated dosing, and screen for potential CYP3A induction as a possible mechanism of reduced systemic exposure of GSK2256098 at Day 15 and later time points. The primary objective of this study is to determine the safety, tolerability, and MTD of GSK2256098.

本研究为针对实体瘤受试者的I期剂量爬坡试验。第一部分将采用剂量爬坡流程确定最大耐受剂量（maximum tolerated dose, MTD）。确定MTD后，第二至第五部分的受试者入组可同步开展。第二部分将进一步探索GSK2256098在已知过表达黏着斑激酶（focal adhesion kinase, FAK）的肿瘤受试者中的安全性、药代动力学（pharmacokinetics, PK）、耐受性及抗肿瘤活性。第三部分将通过在不低于80mg且不高于I期剂量爬坡试验中测试的MTD剂量水平下，评估毛发、皮肤及肿瘤组织中的药效动力学（pharmacodynamic, PD）标志物，以表征生物有效剂量范围。第四部分将进一步探索GSK2256098在复发性多形性胶质母细胞瘤（glioblastoma multiforme, GBM）受试者中的安全性、PK、耐受性及抗肿瘤活性。本研究的主要研究目的为确定GSK2256098的安全性、耐受性及MTD。次要研究目的包括：表征GSK2256098的药代动力学特征；明确生物活性剂量范围；探索GSK2256098的抗肿瘤活性；以及分析GSK2256098的PK、PD与临床终点之间的相关性。第五部分将考察重复给药后GSK2256098的药代动力学变化的时间进程与程度，并筛选潜在的细胞色素P450 3A（CYP3A）诱导作用，以此作为第15天及后续时间点GSK2256098全身暴露量降低的可能机制。本研究的主要研究目的为确定GSK2256098的安全性、耐受性及MTD。