A phase II study of the 5-lipoxygenase inhibitor, CV6504, in advanced pancreatic cancer: Correlation of clinical data with pharmacokinetic and pharmacodynamic endpoints

Purpose: Primary objective was to determine response rate of patients with advanced pancreatic cancer to a novel lipoxygenase and thromboxane A2 synth etase inhibitor (CV6504); secondary objectives included estimation of pharm acokinetics of CV6504, target-enzyme inhibition, safety and tolerance, qual ity of life and survival. Patients and methods: Thirty-one patients with advanced pancreatic cancer w ere planned to receive CV6504, 100 mg TDS, orally for three months, at whic h point CT scans were performed to assess therapeutic response rates. Stead y state concentrations of CV6504 and thromboxane B2 (an indirect measure of thromboxane A2 synthetase (TA(2)S) inhibition) were made. Of the 31 patien ts entered into the study, 23 were considered fully evaluable for response. Results: The drug was well tolerated with few side effects; no partial or c omplete responses were seen, but 10 patients had stable disease at 3 months ; quality of life was maintained during therapy; mean CV6504 steady state p lasma concentrations of 14 +/- 6 ng/ml resulting in 75 +/- 18% inhibition o f TA(2)S were achieved; median-survival time for all patients considered el igible for assessment of efficacy was 36.6 weeks after the initial dose of study medication. The actuarial one-year survival was approximately 25%. Conclusion: CV6504 inhibits its target enzyme in vivo, maintains stable dis ease in 32% of evaluable patients and is well tolerated.