期刊
CLINICAL CANCER RESEARCH
卷 19, 期 7, 页码 1873-1883出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-12-2926
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资金
- NIH [R21 CA115260, R01 CA93738, P30 CA016059, M01RR00065, U01 CA69912, 23XS026, P30 CA15083, P30 CA60516]
Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Experimental Design: Patients received vorinostat (200mgorally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily x 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly x 2. The alvocidib dose was escalated using a standard 3+3 design. Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m(2) (30-minute loading infusion) followed by 20 mg/m(2) (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21(CIP1) induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent. Conclusions: Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules. Clin Cancer Res; 19(7); 1873-83. (C)2013 AACR.
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