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

Purpose: Vorinostat (V) at levels >2.5 μM 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 μM (± 2.8). V C _max ≥2.5 μM 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 ≥2 μM 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 μM. V concentrations higher than previously reported with oral dosing were achieved.