A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia: a NCIC (National Cancer Institute of Canada) Clinical Trials Group Study
A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia: a NCIC (National Cancer Institute of Canada) Clinical Trials Group Study
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DOI：
10.3109/10428190903585286
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发表时间：
2010-02-01
影响因子：
2.6
通讯作者：
Seymour, Lesley
中科院分区：
文献类型：
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作者：
Crump, Michael;Hedley, David;Seymour, Lesley
索拉非尼是RAF激酶、VEGFR-2、c-kit和Flt3的小分子抑制剂。在这项随机的I期研究中，符合条件的患者既有复发/难治性急性髓系白血病(AML)，又有过一次诱导方案，或者年龄为65岁，患有未经治疗的骨髓增生异常综合征(MDS)或继发性AML。每4周口服索拉非尼28天(CONT)或14天(INT)，分3个剂量水平(100、200、400 mg，2次/d)，同时检测300 mg cont。42名患者入选(中位年龄71岁[37-82岁]，化疗前：22岁)。剂量限制毒性(DLT)：100 mg：2/12例；400 mg BID：1/17例。索拉非尼400 mg CONT在该人群中不耐受：6/8因毒性接受了14天的治疗；300 mg CONT未见DLT。1例ALLFlt3-ITD患者出现CR1例。流式细胞仪研究表明索拉非尼通过c-kit抑制ERK的磷酸化。AML的推荐II期剂量为300 mg，连续两次，联合测试和Flt3-ITD AML是有必要的。
Sorafenib is a small molecule inhibitor of RAF kinase, VEGFR-2, c-KIT, and FLT3. In this randomized phase I study, eligible patients had relapsed/refractory acute myeloid leukemia (AML), and one prior induction regimen, or were age > 65 with untreated myelodysplastic syndrome (MDS) or secondary AML. Sorafenib was given orally for 28 days (cont) or 14 days (int) every 4 weeks at three dose levels (100, 200, and 400 mg BID), 300 mg cont was also tested. Forty-two patients were enrolled (median age 71 [37-82],- prior chemotherapy: 22). Dose-limiting toxicity (DLT) was: 100 mg BID: 0/7 patients; 200 mg BID: 2/12 patients; 400 mg BID: 1/17 patients. Sorafenib 400 mg cont was not tolerated in this population: 6/8 received < 14 days of treatment due to toxicity; no DLT was seen with 300 mg cont. One CR was seen in a patient with AML with FLT3-ITD. Flow cytometry studies suggest that sorafenib inhibits ERK phosphorylation via c-KIT. The recommended phase II dose in AML is 300 mg BID continuously, and testing in combination and in FLT3-ITD AML is warranted.