A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors.
A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors.
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DOI：
10.1186/1756-8722-7-22
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发表时间：
2014-03-11
影响因子：
28.5
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zhang J;Cao J;Li J;Zhang Y;Chen Z;Peng W;Sun S;Zhao N;Wang J;Zhong D;Zhang X;Zhang J
AST 1306是一种口服活性的EGFR（erbB 1）、HER 2（erbB 2）和HER 4（erbB 4）信号传导的不可逆小分子抑制剂。这是一项I期、开放标签、剂量递增研究，旨在评估口服AST 1306的安全性和耐受性、药代动力学（PK）和初步抗肿瘤作用。此外，还检测了食物对PK的影响。采用改良的Fibonacci 3 + 3剂量递增设计来确定晚期实体瘤患者的剂量限制性毒性（DLT）和推荐的II期剂量（RP 2D）。研究了以下剂量水平：两个剂量水平（400和800 mg）每日一次（QD），五个剂量水平（600、800、1000、1200和1500 mg）每日两次（BID），三个剂量水平（800、1000和1200 mg）每日三次（TID）。在PK和扩展研究中，在3个剂量水平（最大耐受剂量[MTD]，比MTD低1个或2个剂量水平）中，每个剂量队列至少入组8例患者，以评价PK特征。入组了71例患者，其中乳腺癌（n = 22）和肺癌（n = 14）是最常见的原发性癌症。最常见的药物相关不良事件为1 - 3级腹泻和皮疹，1 - 2级疲乏。在剂量递增期间，关键DLT是在1000 mg BID（n = 1）、1500 mg BID（n = 1）、800 mg TID（n = 1）和1200 mg TID（n = 2）组的5例患者中观察到的3级腹泻。AST 1306吸收迅速，清除率中等至高。在评价的范围内，PK浓度参数随剂量增加而增加，无随时间蓄积的证据。在进食状态下，平均Tmax延长，Cmax增加，AUC 0-∞升高。在55例可评价患者中，7例患者出现部分缓解，包括5例乳腺癌患者、1例肺癌患者和1例胃癌患者。7例患者达到了疾病稳定≥ 6个月的最佳缓解。基于DLT和PK特征，RP 2D定义为1000 mg TID，有初步抗肿瘤活性证据。建议开展进一步研究。
AST1306 is an orally active irreversible small molecule inhibitor of EGFR (erbB1), HER2 (erbB2) and HER4 (erbB4) signaling. This is a phase I, open-label, dose-escalation study to evaluate the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor effects of oral AST1306. In addition the effects of food on PK was tested. A modified Fibonacci 3 plus 3 dose-escalation design was employed to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) in patients with advanced solid tumors. The following dose levels were investigated: once daily (QD) at two dose levels (400-and 800 mg), twice daily (BID) in five dose levels (600-, 800-, 1000-, 1200- and 1500 mg), and three times daily (TID) in three dose levels (800-, 1000- and 1200 mg). In the PK and extension study, at least eight patients per dose cohort in three dose levels (maximum tolerated dose [MTD], one or two doses level lower than the MTD) were enrolled to evaluate the PK profiles. Seventy-one patients were enrolled, with breast (n = 22) and lung cancers (n = 14) being the most common primary cancers. The most frequent drug-related adverse events were grade 1 to 3 diarrhea and rash, grade 1 to 2 fatigue. During dose escalation, the key DLT was grade 3 diarrhea observed in 5 patients at 1000 mg BID (n = 1), 1500 mg BID (n = 1), 800 mg TID (n = 1) and 1200 mg TID (n = 2). AST1306 was rapidly absorbed and had moderate to high clearance. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Under fed conditions, the mean Tmax was prolonged, Cmax was increased, and AUC0-∞ was raised. Of the 55 evaluable patients, 7 patients experienced partial responses, including 5 with breast cancer, 1 with lung cancer, and 1 with gastric cancer. The best response with stable disease for ≥ 6 months was achieved in 7 patients. Based on the DLT and PK profile, the RP2D was defined as 1000 mg TID with evidence of preliminary anti-tumor activity. Further studies are recommended.
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影响因子：
3.4
作者：
Gordon, Michael S.;Mendelson, David S.;Gross, Mitchell;Uttenreuther-Fischer, Martina;Ould-Kaci, Mahmoud;Zhao, Yihua;Stopfer, Peter;Agus, David B.
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158.5
作者：
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Halmos, B
影响因子：
3.4
作者：
Takahashi, Toshiaki;Boku, Narikazu;Murakami, Haruyasu;Naito, Tateaki;Tsuya, Asuka;Nakamura, Yukiko;Ono, Akira;Machida, Nozomu;Yamazaki, Kentaro;Watanabe, Junichiro;Ruiz-Garcia, Ana;Imai, Keiji;Ohki, Emiko;Yamamoto, Nobuyuki
通讯作者：
Yamamoto, Nobuyuki