期刊
INVESTIGATIONAL NEW DRUGS
卷 31, 期 5, 页码 1217-1227出版社
SPRINGER
DOI: 10.1007/s10637-013-9937-8
关键词
Acute leukemia; Akt inhibition; UCN-01; Perifosine
资金
- National Cancer Institute [UO-1 CA062487]
- National Center for Research Resources [M01 RR 16500]
- Keryx/AOI Pharmaceuticals, Inc.
Background The PI3K-Akt pathway is frequently activated in acute leukemias and represents an important therapeutic target. UCN-01 and perifosine are known to inhibit Akt activation. Methods The primary objective of this phase I study was to determine the maximum tolerated dose (MTD) of UCN-01 given in combination with perifosine in patients with advanced acute leukemias and myelodysplastic syndrome. Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and efficacy. Perifosine 150 mg every 6 h was given orally on day 1 followed by 100 mg once a day continuously in 28-day cycles. UCN-01 was given intravenously over 3 h on day 4 at three dose levels (DL1 = 40 mg/m(2); DL2 = 65 mg/m(2); DL3 = 90 mg/m(2)). Results Thirteen patients were treated (DL1, n = 6; DL2, n = 4; DL3, n = 3) according to a traditional 3 + 3 design. Two patients at the DL3 experienced dose-limiting toxicity including grade 3-4 pericardial effusion, hypotension, hyperglycemia, hyperkalemia, constitutional symptoms and grade 5 pneumonitis. Other frequent toxicities were grade 1-2 nausea, diarrhea, vomiting, fatigue and hyperglycemia. The MTD was determined to be UCN-01 65 mg/m(2) with perifosine 100 mg a day. No appreciable direct Akt inhibition could be demonstrated in patients' mononuclear cells using Western blot, however, reduced phosphorylation of the downstream target ribosomal protein S6 in leukemic blasts was noted by intracellular flow cytometry. No objective responses were observed on this study. Conclusion UCN-01 and perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据