Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors
Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors
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DOI：
10.1007/s10637-013-9963-6
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发表时间：
2014-02-01
影响因子：
3.4
通讯作者：
Keilholz, U.
中科院分区：
文献类型：
--
作者：
Tjulandin, S.;Moiseyenko, V.;Keilholz, U.
目的AZD8931是一种口服EGFR(ErbB1)、HER2(ErbB2)和HER3(ErbB3)信号转导的等效性抑制剂。这项I期开放研究评估了AZD8931在晚期实体肿瘤(http://www.clinicaltrials.gov/NCT00637039).)患者中的安全性、耐受性和药代动力学方法用AZD8931单剂口服，观察4d后每日2次给药，连续21d。采用标准的3+3设计，AZD8931剂量从40毫克BID递增到最大耐受量(MTD)。结果28例患者接受AZD8931治疗(5例，40 mg Bid；8例，80 mg Bid；6例，160 mg Bid；6例，240 mg Bid；3例，300 mg Bid)。卵巢(n=8)和乳腺(n=5)是最常见的原发肿瘤类型。最常见的不良事件是急诊皮肤(n=27)和腹泻(n=21)。240毫克BID队列中的1名患者(3级皮疹)和300 mg BID队列中的2名患者(3级和4级腹泻)被确定为剂量限制毒性(DLT)。AZD8931的药代动力学曲线支持每天两次给药。AZD8931吸收迅速(中位数t(Max)1-3h)，分布均匀，具有中等至高的清除能力，消除半衰期约为11h。剂量达160 mg时，AZD8931的吸收呈近似比例增加。在第21天可评估反应的21名患者中，12名病情稳定，9名病情恶化。结论AZD8931的MTD为240 mg，2次/d，但需要更多的长期数据来确定适合于慢性治疗的AZD8931的剂量。
Aim AZD8931 is an oral equipotent inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling. This Phase I, open-label study evaluated the safety, tolerability, and pharmacokinetics of multiple ascending doses of AZD8931 in patients with advanced solid tumors (http://www.clinicaltrials.gov/NCT00637039). Methods Patients received AZD8931 as a single oral dose followed by 4 days of observation, then twice-daily dosing for 21 consecutive days. Using a standard 3 + 3 design, AZD8931 doses were escalated from 40 mg bid until the maximum tolerated dose (MTD) was established. Results Twenty-eight patients received AZD8931 (n = 5, 40 mg bid; n = 8, 80 mg bid; n = 6, 160 mg bid; n = 6, 240 mg bid; n = 3, 300 mg bid). Ovary (n = 8) and breast (n = 5) were the most common primary tumor types. The most frequent adverse events were treatment-emergent cutaneous (n = 27) and diarrhea (n = 21). Dose-limiting toxicities (DLTs) were identified in one patient in the 240 mg bid cohort (Grade 3 rash) and two patients in the 300 mg bid cohort (Grade 3 and 4 diarrhea). The pharmacokinetic profile of AZD8931 supported twice-daily dosing. AZD8931 was rapidly absorbed (median t(max) 1-3 h), was well distributed and had moderate to high clearance with an elimination half-life of approximately 11 h. Exposure appeared to increase approximately proportionally with dose up to 160 mg. Of 21 patients evaluable for response at day 21, 12 had stable disease and nine had disease progression. Conclusion The MTD of AZD8931 determined from the 21-day DLT period was 240 mg bid, although more long-term data are needed to confirm a dose of AZD8931 suitable for chronic treatment.