National Cancer Institute of Canada Clinical Trials Group.
Leuk Lymphoma. 2010 Feb;51(2):252-60. doi: 10.3109/10428190903585286.
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.
索拉非尼是一种 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，合格的患者患有复发/难治性急性髓细胞白血病（AML），并且接受过一次诱导治疗，或年龄>65 岁且未接受治疗的骨髓增生异常综合征（MDS）或继发性 AML。索拉非尼每 4 周口服 28 天（连续）或 14 天（间歇），剂量水平为 3 个（100、200 和 400 mg BID）；也测试了 300 mg 连续用药。共纳入 42 例患者（中位年龄 71 岁[37-82]；既往化疗：22 例）。剂量限制性毒性（DLT）为：100 mg BID：7/7 例患者无 DLT；200 mg BID：12/12 例患者有 DLT；400 mg BID：17/17 例患者有 DLT。索拉非尼 400 mg 连续用药在该人群中不能耐受：由于毒性，6/8 例患者接受的治疗<14 天；300 mg 连续用药未见 DLT。一名伴有 FLT3-ITD 的 AML 患者出现完全缓解。流式细胞术研究表明，索拉非尼通过 c-KIT 抑制 ERK 磷酸化。AML 的推荐 II 期剂量为 300 mg BID 持续用药，有必要进行联合用药和 FLT3-ITD AML 的检测。
