Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
Eur J Cancer. 2013 Mar;49(4):782-9. doi: 10.1016/j.ejca.2012.09.036. Epub 2012 Oct 22.
To determine the maximum tolerated dose (MTD) of OSI-930 that can be combined with erlotinib, and establish recommended phase 2 doses when both agents are administered daily in patients with advanced solid tumours.
Eligible patients with advanced solid tumours were enrolled into this standard "three+three" dose escalation study. Study treatment commenced on day 1 with OSI-930, and erlotinib was introduced on day 8. PK profiles of OSI-930, erlotinib and its active metabolite, OSI-420, were determined. Changes in sVEGFR2 as a pharmacodynamic biomarker of OSI-930 activity were assessed.
Twenty one patients were enrolled to 1 of 3 cohorts: 200 mg OSI-930 BID+100 mg erlotinib QD; 200 mg OSI-930 BID+150 mg erlotinib QD; 300 mg OSI-930 BID+150 mg erlotinib QD. The most common adverse events were anorexia (85%), diarrhoea (75%), rash (70%) and lethargy (65%). The MTD was not reached but the onset of cumulative toxicity necessitating dose modification after the 28-d DLT assessment period was common at the highest dose level. A PK interaction was identified with co-administration of both agents resulting in a two-fold increase in OSI-930 exposure. Pharmacodynamic activity was observed with a decline in sVEGFR levels detected in all patients. Ten patients had disease stabilization (median duration 119 d).
200 mg OSI-930 BID+150 mg erlotinib QD were the recommended doses for further evaluation of this combination.
确定与厄洛替尼联合使用时 OSI-930 的最大耐受剂量（MTD），并确定这两种药物每日联合给药时治疗晚期实体瘤患者的推荐 2 期剂量。
本标准“3+3”剂量递增研究纳入了符合条件的晚期实体瘤患者。研究治疗于第 1 天开始给予 OSI-930，第 8 天开始给予厄洛替尼。测定 OSI-930、厄洛替尼及其活性代谢物 OSI-420 的 PK 特征。评估 OSI-930 活性的药效学生物标志物 sVEGFR2 的变化。
21 例患者入组 3 个队列之一：200mg OSI-930 BID+100mg 厄洛替尼 QD；200mg OSI-930 BID+150mg 厄洛替尼 QD；300mg OSI-930 BID+150mg 厄洛替尼 QD。最常见的不良反应是厌食（85%）、腹泻（75%）、皮疹（70%）和乏力（65%）。未达到 MTD，但在 28 天 DLT 评估期后因累积毒性而需要调整剂量的起始剂量较高。同时给予两种药物时发现 PK 相互作用，导致 OSI-930 暴露增加一倍。在所有患者中均观察到药效学活性，sVEGFR 水平下降。10 例患者疾病稳定（中位持续时间 119d）。
200mg OSI-930 BID+150mg 厄洛替尼 QD 是进一步评估该联合用药的推荐剂量。
