A phase I study of zibotentan (ZD4054) in patients with metastatic, castrate-resistant prostate cancer.

PURPOSE: To assess the maximum well-tolerated dose (MWTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and pharmacodynamics of zibotentan, a novel specific endothelin-A receptor antagonist, in patients with metastatic prostate cancer.

METHODS

Patients with metastatic, castrate-resistant prostate cancer (CRPC) were treated with escalating doses of oral zibotentan (ZD4054) 10-200 mg once daily. The initial cohort received 28 daily doses (Period 1). Patients who had evidence of clinical benefit and who had not met any of the criteria for withdrawal were allowed to receive zibotentan at their current dose level until they no longer derived clinical benefit (Period 2). PK of zibotentan and changes in prostate-specific antigen and bone markers were also assessed.

RESULTS

Sixteen patients were evaluable for the safety and single-dose PK analyses. Eleven patients completed Period 1, and nine patients proceeded to Period 2. DLTs were encountered at 22.5 mg; one patient had grade 3 dyspnea and peripheral edema and a second patient had grade 3 headache and intraventricular hemorrhage. Enrollment was expanded at the 15 mg dose level to further determine the safety and tolerability of zibotentan. No DLTs were seen at 15 mg, and the most frequent adverse events were headache, peripheral edema, fatigue, nasal congestion and nausea.

CONCLUSIONS

The MWTD for zibotentan was 15 mg orally daily. The predominant adverse events observed were consistent with those reported for this class of drugs, and prolonged stable disease was noted in some patients. Phase III studies with zibotentan in men with metastatic CRPC are ongoing.