Division of Hematologic Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Leukemia. 2010 Aug;24(8):1437-44. doi: 10.1038/leu.2010.132. Epub 2010 Jun 10.
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 >or=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.
我们报告了多激酶抑制剂索拉非尼在复发性和难治性急性白血病患者中使用间歇给药方案的 I 期剂量递增试验结果。15 名晚期白血病患者（12 名急性髓细胞白血病、2 名急性淋巴细胞白血病、1 名双表型），中位年龄 63 岁（范围 37-85 岁），入组并接受剂量递增试验治疗。55%的周期出现>或=3 级毒性，最大耐受剂量（MTD）确定为 400mg 每日两次×21 天，28 天为一个周期。激酶靶点细胞外信号调节激酶（ERK）和 FLT3 内部串联重复（ITD）的血浆抑制测定显示出优异的靶抑制作用，FLT3-ITD 沉默发生在 MTD 以下。索拉非尼的 N-氧化物代谢物似乎比母体化合物更能抑制 FLT3-ITD。尽管体外 FLT-3 ITD 抑制明显，但在这项单药研究中，没有患者符合完全或部分缓解的标准。在 15 名患者中，11 名患者的最佳反应为病情稳定。尽管索拉非尼在这一治疗密集的人群中作为单一药物仅表现出适度的临床活性，但对 FLT3 和 ERK 的强烈抑制表明，在联合治疗中可能具有潜在的重要作用。
