期刊
LEUKEMIA & LYMPHOMA
卷 51, 期 2, 页码 252-260出版社
TAYLOR & FRANCIS LTD
DOI: 10.3109/10428190903585286
关键词
RAF; RAS; phase I; leukemia; signal transduction
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.
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