14602 Background: Endothelin (ET)-1 and its primary receptor, the ETA receptor, contribute to tumor cell growth, survival, angiogenesis and invasion. Atrasentan is a highly potent, selective ETA receptor antagonist. This study assessed safety and pharmacokinetics (PK) in Japanese patients with hormone refractory prostate cancer. Methods: This open-label, single-center Phase I trial evaluated the safety and PK of escalating oral atrasentan doses (2.5, 10 or 20 mg) given daily on day 1 and day 4 through 27 (except day 2 and 3). Dose-limiting toxicity (DLT) was defined as Grade 3 or greater adverse events related to study drug. Results: Eighteen patients, aged 54–74 (median; 66) were treated in cohorts of 6 patients each. The compliance of all patients was 100%. The most common toxicities were rhinitis, peripheral edema, headache, hypotension and anemia, all of which were well tolerated. These events were consistent with the anticipated vasodilatory effects or with a hemodilution effect of the study drug. DLTs were not observed. Atrasentan was rapidly absorbed following oral administration of 2.5 to 20 mg, maximum plasma concentrations averaged from 0.4 to 0.8 hours. After peaking, plasma concentrations declined bi-exponentially with a terminal half-life of approximately 25 hours. In the 10 mg dosing group, the steady-state maximum plasma concentration (Cmax) and the area under the curve (AUC0–24h) averaged 135.5 ng/mL and 533 ng h/mL, respectively. The Cmax and AUC values generally increased linearly with increasing dose after single- and multiple-dose administration. Compared to baseline, PSA decreased 50% or more in 1 patient (20 mg) and increased 25% or more in 10 patients (2.5 mg;2, 10 mg;5, 20 mg;3). The PSA of the remaining 7 patients (2.5 mg;4, 10 mg;1, 20 mg;2) ranged from < 25% increase to < 50% decrease. Fourteen patients continued on study drug in an extension study. Conclusions: Atrasentan is well tolerated, with no dose-limiting adverse events observed up to 20 mg in Japanese patients. The main adverse events are consistent with the vasodilatory effect of the drug. PK are linear and dose-proportional; the half-life is appropriate for once-daily dosing. No significant financial relationships to disclose.