TY - JOUR
T1 - A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors
AU - Dickson, Mark Andrew
AU - Rathkopf, Dana E.
AU - Carvajal, Richard D.
AU - Grant, Steven
AU - Roberts, John D.
AU - Reid, Joel M.
AU - Ames, Matthew M.
AU - McGovern, Renee M.
AU - Lefkowitz, Robert A.
AU - Gonen, Mithat
AU - Cane, Lauren M.
AU - Dials, Heather J.
AU - Schwartz, Gary K.
N1 - Funding Information:
received research funding from Merck & Co. The other authors report no conflicts of interest.
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
KW - CDKs and CDK inhibitors
KW - Combination chemotherapy
KW - Histone deacetylase inhibitors
KW - Pharmacokinetics
KW - Phase I trials
UR - http://www.scopus.com/inward/record.url?scp=83455236337&partnerID=8YFLogxK
U2 - 10.1007/s10637-010-9447-x
DO - 10.1007/s10637-010-9447-x
M3 - Article
C2 - 20461440
AN - SCOPUS:83455236337
SN - 0167-6997
VL - 29
SP - 1004
EP - 1012
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 5
ER -