A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours.
A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours.
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DOI：
10.1038/sj.bjc.6604108
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发表时间：
2008-01-15
影响因子：
8.8
通讯作者：
de Vries, Ege
中科院分区：
文献类型：
--
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
评估表皮生长因子受体（EGFR）1和2（HER2）酪氨酸激酶双重抑制剂BIBW 2992的耐受性、药代动力学（PK）、药效学（PD）和临床活性。探索了BIBW 2992每日一次（OD）给药14天，随后停药14天的递增方案。38例患者入组。剂量水平为10、20、30、45、70、85和100 mg。在100 mg剂量下，2例患者发生剂量限制性毒性（DLT）（常见毒性标准3级皮疹和3级腹泻，尽管接受了洛哌丁胺治疗）。在下一个较低剂量70 mg中，6例患者中有1例发生DLT（3级疲乏和ALAT升高）。研究了85 mg的中间剂量水平。在此，2例患者发生DLT（尽管接受了治疗，但仍发生3级腹泻，尽管接受了治疗，但仍发生持续7天以上的2级腹泻）。另外12例患者接受70 mg治疗。BIBW 2992单次和多次给药后的PK显示吸收中等速度，且未偏离剂量比例。皮肤活检的药效学分析未显示EGFR相关生物标志物的显著变化。然而，观察到对表皮角质形成细胞增殖指数的显著抑制作用。未观察到部分或完全缓解，在7例患者中观察到持续超过4个周期的稳定疾病。BIBW 2992治疗14天，随后停药14天的研究的推荐剂量为70 mg OD。
To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.
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影响因子：
45.3
作者：
Baselga, J;Rischin, D;Albanell, J
通讯作者：
Albanell, J
DOI：
10.1073/pnas.0502860102
发表时间：
2005-05-24
影响因子：
11.1
作者：
Kwak, EL;Sordella, R;Haber, DA
通讯作者：
Haber, DA
影响因子：
11.5
作者：
Munster, Pamela N.;Britten, Carolyn D.;Tolcher, Anthony W.
通讯作者：
Tolcher, Anthony W.
影响因子：
82.9
作者：
Torrance, CJ;Jackson, PE;Discafani, CM
通讯作者：
Discafani, CM
DOI：
10.1073/pnas.0504952102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Carter, TA;Wodicka, LM;Lockhart, DJ
通讯作者：
Lockhart, DJ