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

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue, K6/534 CSC, Madison, WI 53792, USA.
Investigational New Drugs (Impact Factor: 2.92). 09/2009; 29(1):118-25. DOI: 10.1007/s10637-009-9318-5
Source: PubMed


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.
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.
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.
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.

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    • "Ratios of geometric means of each hepatically impaired group compared to the normal function group (mild/moderate/severe: control) and 90% confidence intervals (CIs) were reported. An effect of hepatic impairment was predefined to have occurred if the upper 90% CI for the ratio did not lie below 2. This was chosen as zibotentan 15 mg has previously been tolerated in patients with CRPC; however, zibotentan 22.5 mg was not tolerated, therefore doubling of the zibotentan dose was to be eliminated [30]. "
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