A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias

被引：96

作者：

Pratz, K. W. ^{[1
]}

Cho, E. ^{[1
]}

Levis, M. J. ^{[1
]}

Karp, J. E. ^{[1
]}

Gore, S. D. ^{[1
]}

McDevitt, M. ^{[1
]}

Stine, A. ^{[1
]}

Zhao, M. ^{[1
]}

Baker, S. D. ^{[2
]}

Carducci, M. A. ^{[1
]}

Wright, J. J. ^{[3
]}

Rudek, M. A. ^{[1
]}

Smith, B. D. ^{[1
]}

机构：

[1] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Oncol, Div Hematol Malignancies, Baltimore, MD 21231 USA

[2] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

[3] NCI, Invest Drug Branch, Bethesda, MD 20892 USA

来源：

LEUKEMIA | 2010年 / 24卷 / 08期

基金：

美国国家卫生研究院;

关键词：

acute myeloid leukemia; FLT3 targeted therapy; signal transduction inhibitors; clinical trial; ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; FACTOR RECEPTOR INHIBITOR; DAYS ON/7 DAYS; SOLID TUMORS; PHASE-I; RAF KINASE; ANTITUMOR-ACTIVITY; FLT3; INHIBITORS;

D O I：

10.1038/leu.2010.132

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities >= grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. x 21 days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies. Leukemia (2010) 24, 1437-1444; doi:10.1038/leu.2010.132; published online 10 June 2010

引用

页码：1437 / 1444

页数：8

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