A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours.
A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours.
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DOI：
10.1038/bjc.2012.154
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发表时间：
2012-05-08
影响因子：
8.8
通讯作者：
Evans, T. R. J.
中科院分区：
文献类型：
--
作者：
Boss, D. S.;Glen, H.;Beijnen, J. H.;Keesen, M.;Morrison, R.;Tait, B.;Copalu, W.;Mazur, A.;Wanders, J.;O'Brien, J. P.;Schellens, J. H. M.;Evans, T. R. J.
该I期研究的目的是评估E7080在晚期难治性实体肿瘤患者中的安全性和耐受性；确定E7080的最大耐受剂量（MTD）和药代动力学特征；并探索其抗肿瘤功效的初步证据。符合条件的患者口服E7080，剂量逐渐递增，每日一次连续用药，疗程为28天。在第1周期第1、8、15、22天和第2周期第1天采集样品进行药代动力学分析。每两个周期评估一次抗肿瘤疗效。82例患者接受E7080治疗，剂量从0.2到32毫克。剂量限制性毒性为32 mg时的3级蛋白尿（2例患者），MTD定义为25 mg。最常见的累积毒性（所有级别）是高血压（40%的患者）、腹泻（45%）、恶心（37%）、口炎（32%）和呕吐（23%）。7名患者（9%）部分缓解，38名患者（46%）病情稳定为最佳缓解。E7080具有剂量线性动力学，给药4周后无药物积累。E7080在每天25毫克的剂量下耐受性良好。在黑色素瘤和肾细胞癌患者中观察到令人鼓舞的抗肿瘤疗效。
The objectives of this phase I study were to assess the safety and tolerability of E7080 in patients with advanced, refractory solid tumours; to determine the maximum tolerated dose (MTD) and pharmacokinetics profile of E7080; and to explore preliminary evidence of its anti-tumour efficacy. E7080 was administered orally in escalating doses on a once-daily continuous schedule in 28-day cycles to eligible patients. Samples for pharmacokinetic analyses were collected on days 1, 8, 15 and 22 of cycle 1 and day 1 of cycle 2. Anti-tumour efficacy was assessed every two cycles. Eighty-two patients received E7080 in dose cohorts from 0.2 to 32 mg. Dose-limiting toxicities were grade 3 proteinuria (two patients) at 32 mg, and the MTD was defined as 25 mg. The most frequently observed cumulative toxicities (all grades) were hypertension (40% of patients), diarrhoea (45%), nausea (37%), stomatitis (32%) and vomiting (23%). Seven patients (9%) had a partial response and 38 patients (46%) had stable disease as best response. E7080 has dose-linear kinetics with no drug accumulation after 4 weeks’ administration. E7080 is well tolerated at doses up to 25 mg per day. Encouraging anti-tumour efficacy was observed in patients with melanoma and renal cell carcinoma.
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影响因子：
158.5
作者：
Horstmann, E;McCabe, MS;Grady, C
通讯作者：
Grady, C
影响因子：
3.3
作者：
Mehnert, Janice M.;McCarthy, Mary M.;Jitaveanu, Lucia;Flaherty, Keith T.;Aziz, Saadia;Camp, Robert L.;Rimm, David L.;Kluger, Harriet M.
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Kluger, Harriet M.
影响因子：
8.8
作者：
Kamba, T;McDonald, D M
通讯作者：
McDonald, D M
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158.5
作者：
Motzer, Robert J.;Hutson, Thomas E.;Figlin, Robert A.
通讯作者：
Figlin, Robert A.
影响因子：
158.5
作者：
Hurwitz, H;Fehrenbacher, L;Kabbinavar, F
通讯作者：
Kabbinavar, F