PI‐13

BACKGROUND To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of CP‐724714, a novel HER2 tyrosine kinase inhibitor under development for the treatment of advanced HER2‐overexpressing cancers. METHODS This was an open label First‐in‐Humans dose‐escalation study of continuous oral dosing of CP‐724714 in repeating 21‐day cycles in 30 cancer patients. Dose cohorts of 250 mg QD, 250 mg BID, 250 mg TID, and 400 mg BID were evaluated. Serum concentrations of CP‐724714 were obtained after single dose and at steady state. PK parameters were determined by non‐compartmental methods. RESULTS CP‐724714 was rapidly absorbed with median Tmax ∼1 to 2 hours. Mean Cmax and AUC increased in an approximate dose proportional manner. Inter‐patient variability in PK parameters was moderate (CV: 31–65%). There was some accumulation with BID and TID dosing with a mean AUC accumulation ratio ∼1.2–1.5, which was consistent with the mean t1/2 (∼4.5 h). 250 mg BID was identified as the MTD. With this dosing regimen, the mean steady state exposure exceeded the predicted efficacious level based on preclinical models. The major toxicity was liver enzyme elevation. Analysis of safety data revealed increasing liver enzymes and bilirubin with increasing PK exposures. CONCLUSIONS Systemic exposure parameters increased with dose. Systemic exposure at the MTD exceeded the predicted efficacious level, which supports evaluation of CP‐724714 efficacy in Phase 2 studies. Clinical Pharmacology & Therapeutics (2005) 79 , P10–P10; doi: 10.1016/j.clpt.2005.12.034