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Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Atrasentan

An Endothelin Receptor Antagonist for Refractory Prostate Cancer¹

Department of Internal Medicine, University Hospital, 3584 CX Utrecht, the Netherlands [B. A. Z., G. G., E. V.], and Abbott Laboratories, Abbott Park, Illinois [T. J. J., R. A. H., J. D. I., R. A. C., T. W. L.]

Purpose: Evidence suggests that endothelin (ET)-1 and its primary receptor, the ET_A receptor, may contribute to the progression of prostate and other cancers. Atrasentan (ABT-627) is a highly potent, selective ET_A receptor antagonist. This study assessed safety, maximum tolerated dose, and pharmacokinetics (PK) in patients with refractory adenocarcinomas, primarily prostate cancer.

Experimental Design: This 28-day, single-center Phase I trial evaluated the safety and PK of escalating oral atrasentan doses (2.5–95 mg) given daily (except day 2) to eligible patients 18 years old with an adenocarcinoma proven resistant to standard therapy. Priority was given to patients with hormone-refractory prostate cancer. After 28 days, patients without objective signs of tumor progression were eligible to continue atrasentan in an extension study.

Results: Thirty-nine patients (30 of whom had prostate cancer) were treated in cohorts of three patients each with escalating atrasentan doses (2.5, 5, 10, 20, 30, 45, 60, 75, and 95 mg). The most common adverse events were rhinitis, headache, and peripheral edema. Anemia consistent with a reversible hemodilution effect was observed. No maximum tolerated dose was found in the dose range studied. Atrasentan PK were characterized by rapid absorption (mean T_max = 0.9 h), mean ± SD oral clearance of 24 ± 15 liters/h, and volume distribution of 726 ± 477 liters. PK were approximately dose-proportional and time independent across doses.

Conclusions: Atrasentan is well tolerated, with no dose-limiting adverse events observed up to 95 mg. 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.

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