A phase II study of the 5-lipoxygenase inhibitor, CV6504, in advanced pancreatic cancer: correlation of clinical data with pharmacokinetic and pharmacodynamic endpoints.
OBJECTIVE
Primary objective was to determine response rate of patients with advanced pancreatic cancer to a novel lipoxygenase and thromboxane A2 synthetase inhibitor (CV6504); secondary objectives included estimation of pharmacokinetics of CV6504, target-enzyme inhibition, safety and tolerance, quality of life and survival.


METHODS
Thirty-one patients with advanced pancreatic cancer were planned to receive CV6504, 100 mg TDS, orally for three months, at which point CT scans were performed to assess therapeutic response rates. Steady state concentrations of CV6504 and thromboxane B2 (an indirect measure of thromboxane A2 synthetase (TA2S) inhibition) were made. Of the 31 patients entered into the study, 23 were considered fully evaluable for response.


RESULTS
The drug was well tolerated with few side effects; no partial or complete responses were seen, but 10 patients had stable disease at 3 months; quality of life was maintained during therapy; mean CV6504 steady state plasma concentrations of 14 +/- 6 ng/ml resulting in 75 +/- 18% inhibition of TA2S were achieved; median-survival time for all patients considered eligible for assessment of efficacy was 36.6 weeks after the initial dose of study medication. The actuarial one-year survival was approximately 25%.


CONCLUSIONS
CV6504 inhibits its target enzyme in vivo, maintains stable disease in 32% of evaluable patients and is well tolerated.
Ferry
D R
DR
CRC Institute for Cancer Studies, Medical School, University of Birmingham, Edgbaston, UK.
Deakin
M
M
Baddeley
J
J
Daryanani
S
S
Bramhall
S
S
Anderson
D A
DA
Wakelam
M J
MJ
Doran
J
J
Pemberton
G
G
Young
A M
AM
Buckels
J
J
Kerr
D J
DJ
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016227:Benzoquinones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D019787:Linoleic Acid / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D016859:Lipoxygenase Inhibitors; C067513:CV 6504; D013929:Thromboxane B2; D019787:Linoleic Acid