The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2010 Jan 1;16(1):279-90. doi: 10.1158/1078-0432.CCR-09-1675. Epub 2009 Dec 22.
Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti-epidermal growth factor receptor monoclonal antibody panitumumab in advanced non-small cell lung cancer (NSCLC).
Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line).
Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively.
Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC.
Motesanib 是一种小分子血管内皮生长因子受体 1、2 和 3、血小板衍生生长因子受体和 Kit 的拮抗剂。这项 1b 期研究评估了 motesanib 联合卡铂/紫杉醇和/或完全人源抗表皮生长因子受体单克隆抗体 panitumumab 治疗晚期非小细胞肺癌（NSCLC）的安全性、最大耐受剂量（MTD）和药代动力学，并探索了客观反应。
无法切除的 NSCLC 患者连续接受递增剂量的 motesanib [50、125mg 每日一次；75mg 每日两次] 口服连续治疗，加用卡铂/紫杉醇（A 组；一线）或 panitumumab（B 组；一线和二线），每 21 天周期一次，或 125mg 每日一次加用卡铂/紫杉醇和 panitumumab（C 组；一线）。
45 例患者接受了 motesanib 治疗。发生了 3 例剂量限制性毒性：4 级肺栓塞（n=1；A 组，50mg 每日一次）和 3 级深静脉血栓形成（n=2；A 组，125mg 每日一次；C 组）。MTD 为 125mg 每日一次。常见的 motesanib 相关不良事件有疲劳（60%的患者）、腹泻（53%）、高血压（38%）、厌食（27%）和恶心（22%）。3 例胆囊炎发生，但仅发生在 75mg 每日两次的方案中，随后该方案被停用。在 125mg 每日一次时，motesanib 药代动力学与卡铂/紫杉醇联合用药时没有明显变化，但紫杉醇的暴露量略有增加。A、B 和 C 组的客观缓解率分别为 17%、0%和 17%。
motesanib 联合卡铂/紫杉醇和/或 panitumumab 治疗耐受性良好，在 125mg 每日一次的剂量水平下对 motesanib 药代动力学影响不大。这一剂量正在一项正在进行的 NSCLC 三期研究中进行评估。
