A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors

作者：Dickson Mark Andrew; Rathkopf Dana E; Carvajal Richard D; Grant Steven; Roberts John D; Reid Joel M; Ames Matthew M; McGovern Renee M; Lefkowitz Robert A; Gonen Mithat; Cane Lauren M; Dials Heather J; Schwartz Gary K^*

来源：Investigational New Drugs, 2011, 29(5): 1004-1012.

DOI：10.1007/s10637-010-9447-x

• CDKs and CDK inhibitors
• Histone deacetylase inhibitors
• Phase I trials
• Combination chemotherapy
• Pharmacokinetics

Purpose Vorinostat (V) at levels > 2.5 A mu M enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis. Experimental Design One week before combination treatment, V alone was given daily for 3d (cycle -1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15-17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied. Results 34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m(2) bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m(2) over 30 min and 30 mg/m(2) over 4 h. V C(max) at the 800 mg dose was 4.8 A mu M (+/- 2.8). V C(max) a parts per thousand yen2.5 A mu M was achieved in 86% of patients at the MTD. F increased the C(max) of V by 27% (95% CI 11%-43%). F C(max) of a parts per thousand yen2 A mu M was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6-13.2 m). Conclusions Intermittent high dose oral V in combination with F is feasible and achieves target serum levels > 2.5 A mu M. V concentrations higher than previously reported with oral dosing were achieved.

• 出版日期2011-10