Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors.
Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors.
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DOI：
10.4143/crt.2017.303
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发表时间：
2018-07
影响因子：
4.6
通讯作者：
Bang YJ
中科院分区：
文献类型：
--
作者：
Kim TM;Lee KW;Oh DY;Lee JS;Im SA;Kim DW;Han SW;Kim YJ;Kim TY;Kim JH;Han H;Kim WH;Bang YJ
Poziotinib是一种泛人类表皮生长因子受体2（HER）酪氨酸激酶抑制剂，在体外对野生型表皮生长因子受体（EGFR）家族激酶（包括EGFR、HER 2和HER 4）和EGFR突变细胞显示出强效活性。进行了两项I期研究，以确定最大耐受剂量（MTD）、药代动力学、安全性和对晚期实体瘤的抗肿瘤活性。研究了使用两种不同给药方案的标准3+3剂量递增方案：每日一次，给药14天，停药7天（间歇方案）;以及每日一次连续给药，伴有食物效应。其他患者入组扩展队列。两项研究共入组75例患者。最常见的药物相关治疗后出现的不良事件为腹泻、皮疹、口腔炎、瘙痒和厌食。剂量限制性毒性为间歇给药方案中的3级腹泻和连续给药方案中的3级厌食和腹泻。间歇给药方案中的MTD确定为24 mg/天，连续给药方案中的MTD确定为18 mg/天。在间歇方案中，51例可评价患者中分别有8例（16%）和24例（47%）达到部分缓解（PR）和疾病稳定（SD）。在连续给药方案中，19例可评价患者中分别有4例（21%）和6例（32%）达到PR和SD。PR（n=7）或SD ≥ 12周（n=7）的患者出现HER 2扩增（n=7;乳腺癌，5例;胃癌，2例）和EGFR扩增（n=1，鳞状细胞肺癌）。Poziotinib在晚期实体瘤患者中安全且耐受性良好。它对EGFR突变和HER 2扩增的癌症显示出令人鼓舞的活性。
Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors. Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort. A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Dose-limiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer). Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.
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影响因子：
6.4
作者：
Cha, Mi Young;Lee, Kwang-Ok;Kim, Maeng Sup
通讯作者：
Kim, Maeng Sup
影响因子：
9.7
作者：
Nam, Hyun-Jin;Kim, Hwang-Phill;Bang, Yung-Jue
通讯作者：
Bang, Yung-Jue
DOI：
10.1093/jnci/92.3.205
发表时间：
2000-02-02
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Therasse, P;Arbuck, SG;Gwyther, SG
通讯作者：
Gwyther, SG
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
8.8
作者：
Eskens, Falm;Mom, C. H.;Planting, A. S. T.;Gietema, J. A.;Amelsberg, A.;Huisman, H.;van Doorn, L.;Burger, H.;Stopfer, P.;Verweij, J.;de Vries, Ege
通讯作者：
de Vries, Ege