A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors

doi:10.1186/1756-8722-7-22

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	A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors
	Zhang, Jian 2,3; Cao, Junning 2,3; Li, Jin 2,3; Zhang, Yifan5 ; Chen, Zhiyu 2,3; Peng, Wei 2,3; Sun, Si 2,3; Zhao, Naiqing 1; Wang, Jiachen 2,3; Zhong, Dafang5
刊名	JOURNAL OF HEMATOLOGY & ONCOLOGY
	2014-03-11
卷号	7
关键词	AST1306 ErbB family Irreversible tyrosine kinase inhibitor Phase I
ISSN号	1756-8722
DOI	10.1186/1756-8722-7-22
文献子类	Article
英文摘要	Background: 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. Methods: 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. Results: 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 T-max was prolonged, C-max was increased, and AUC(0-8) 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. Conclusions: 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.
WOS关键词	GROWTH-FACTOR RECEPTOR ; CELL LUNG-CANCER ; ACQUIRED-RESISTANCE ; DOSE-ESCALATION ; LAPATINIB GW572016 ; NERATINIB HKI-272 ; ERBB FAMILY ; OPEN-LABEL ; BIBW 2992 ; GEFITINIB
WOS研究方向	Oncology ; Hematology
语种	英语
出版者	BIOMED CENTRAL LTD
WOS记录号	WOS:000334636000001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277155]
专题	上海药物代谢研究中心
通讯作者	Cao, Junning
作者单位	1.Fudan Univ, Sch Publ Hlth, Dept Biostat, Shanghai 200433, Peoples R China; 2.Fudan Univ, Shanghai Med Med, Dept Oncol, Shanghai 200433, Peoples R China; 3.Fudan Univ, Shanghai Canc Ctr, Dept Med Oncol, Shanghai 200433, Peoples R China; 4.Shanghai Allist Pharmaceut, Shanghai, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China;
推荐引用方式 GB/T 7714	Zhang, Jian,Cao, Junning,Li, Jin,et al. A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors[J]. JOURNAL OF HEMATOLOGY & ONCOLOGY,2014,7.
APA	Zhang, Jian.,Cao, Junning.,Li, Jin.,Zhang, Yifan.,Chen, Zhiyu.,...&Zhang, Jing.(2014).A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors.JOURNAL OF HEMATOLOGY & ONCOLOGY,7.
MLA	Zhang, Jian,et al."A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors".JOURNAL OF HEMATOLOGY & ONCOLOGY 7(2014).