Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome.
Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome.
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DOI：
10.1007/s10637-013-9937-8
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发表时间：
2013-10
影响因子：
3.4
通讯作者：
Sausville, Edward A.
中科院分区：
文献类型：
--
作者：
Gojo, Ivana;Perl, Alexander;Luger, Selina;Baer, Maria R.;Norsworthy, Kelly J.;Bauer, Kenneth S.;Tidwell, Michael;Fleckinger, Stephanie;Carroll, Martin;Sausville, Edward A.
PI3K-Akt通路在急性白血病中经常被激活，并且代表重要的治疗靶点。已知UCN-01和哌立福辛抑制Akt活化。这项I期研究的主要目的是确定UCN-01与哌立福新联合治疗晚期急性白血病和骨髓增生异常综合征患者的最大耐受剂量（MTD）。次要目的包括安全性、药代动力学、药效学和疗效。哌立福新150 mg，每6小时口服一次，第1天开始，随后100 mg，每日1次，连续28天为1周期。在第4天，以三种剂量水平（DL1 = 40 mg/m2; DL2 = 65 mg/m2; DL3 = 90 mg/m2）在3小时内静脉给予UCN-01。根据传统的"3 + 3"设计治疗13名患者（DL1，n = 6; DL2，n = 4; DL3，n = 3）。DL3组的2例患者出现剂量限制性毒性，包括3 - 4级心包积液、低血压、高血糖、高钾血症、全身症状和5级肺炎。其他常见毒性为1 - 2级恶心、腹泻、呕吐、疲劳和高血糖。MTD确定为UCN-01 65 mg/m2，哌立福新100 mg/天。使用Western印迹法在患者的单核细胞中不能证明明显的直接Akt抑制，然而，通过细胞内流式细胞术注意到白血病母细胞中下游靶核糖体蛋白S6的磷酸化减少。本研究未观察到客观反应。UCN-01和哌立福新可以安全地施用，但该方案缺乏临床疗效。这种方法可能由于体内Akt抑制不足而失败。
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. 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 hours 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 hours on day 4 at three dose levels (DL1=40 mg/m2; DL2=65 mg/m2; DL3=90 mg/m2). 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/m2 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. 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.
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影响因子：
4.7
作者：
Fu S;Hennessy BT;Ng CS;Ju Z;Coombes KR;Wolf JK;Sood AK;Levenback CF;Coleman RL;Kavanagh JJ;Gershenson DM;Markman M;Dice K;Howard A;Li J;Li Y;Stemke-Hale K;Dyer M;Atkinson E;Jackson E;Kundra V;Kurzrock R;Bast RC Jr;Mills GB
通讯作者：
Mills GB
影响因子：
20.3
作者：
Kornblau, Steven M.;Womble, Matthew;Andreeff, Michael
通讯作者：
Andreeff, Michael
影响因子：
20.3
作者：
Gutierrez, Alejandro;Sanda, Takaomi;Look, A. Thomas
通讯作者：
Look, A. Thomas
影响因子：
3.2
作者：
Morishita, Naoto;Tsukahara, Hirokazu;Morishima, Tsuneo
通讯作者：
Morishima, Tsuneo
NOTCH1、FBW7 和 PTEN 突变对儿童 T 细胞急性淋巴细胞白血病预后和下游信号传导的影响：儿童肿瘤学组的报告。
影响因子：
11.4
作者：
Gedman, A. Larson;Chen, Q.;Desmoulin, S. Kugel;Ge, Y.;LaFiura, K.;Haska, C. L.;Cherian, C.;Devidas, M.;Linda, S. B.;Taub, J. W.;Matherly, L. H.
通讯作者：
Matherly, L. H.