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


METHODS
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.
Dickson
Mark Andrew
MA
Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Rathkopf
Dana E
DE
Carvajal
Richard D
RD
Grant
Steven
S
Roberts
John D
JD
Reid
Joel M
JM
Ames
Matthew M
MM
McGovern
Renee M
RM
Lefkowitz
Robert A
RA
Gonen
Mithat
M
Cane
Lauren M
LM
Dials
Heather J
HJ
Schwartz
Gary K
GK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077337:Vorinostat
D000970:Antineoplastic Agents; D005419:Flavonoids; D006877:Hydroxamic Acids; D010880:Piperidines; C077990:alvocidib; D000077337:Vorinostat
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