A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial
A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial
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DOI：
10.3109/0284186x.2015.1049290
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发表时间：
2016-02-01
期刊：
影响因子：
3.1
通讯作者：
Bergqvist, Michael
中科院分区：
文献类型：
--
作者：
Ekman, Simon;Harmenberg, Johan;Bergqvist, Michael
背景资料。为评价口服小分子胰岛素样生长因子-1受体途径调节剂AXL1717治疗晚期实体瘤的安全性、有效性和药代动力学特性，采用Ia/b期剂量递增研究方法。这是一项前瞻性、单臂、开放标签、剂量发现的Ia/b期研究，目的是单日给药(Ia期)以确定多天给药的起始剂量(Ib期)，以及Ib期以定义和确认推荐的II期剂量(RP2D)以及如果可能的话，重复给药的最大耐受剂量(MTD)。Ia期纳入了16名患者，成功地将剂量提升到2900 mg Bid，没有任何剂量限制性毒性(DLT)。共有39名患者在Ib期接受治疗。AXL1717对中性粒细胞减少症的耐受性良好，是唯一与剂量相关的可逆DLT。RP2D剂量为390 mg，2次/d，疗程4周。一些患者，主要是非小细胞肺癌患者，显示出临床受益的迹象，包括4例部分肿瘤反应(1例根据RECIST，3例根据PET)。单药AXL1717三四线治疗NSCLC患者15例，中位无进展生存期31周，总生存期60周。服用AXL1717的患者粒细胞IGF-1R表达下调，血清游离IGF-1水平升高。AXL1717具有可接受的安全性，并在经过大量预治疗的患者队列中显示出良好的疗效，特别是在非小细胞肺癌患者中。RP2D为390 mg，2次/d，疗程4周。试用号为NCT01062620。
Background. A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors.Material and methods. This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing.Results and Conclusion. Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.