Background: The prognosis for patients with castration-resistant prostate cancer (CRPC) remains suboptimal and targeted therapies should be explored. One potential target is the receptor for luteinizing hormone-releasing hormone (LHRH-R), which is highly expressed on prostate cancer cells. AEZS-108 (AN-152) is an LHRH-cytotoxic hybrid whose rational design covalently couples an LHRH agonist and the cytotoxic doxorubicin. AEZS-108 exploits the presence of these receptors to target delivery of the cytotoxic. We report the phase I trial of AEZS-108 in men with taxane-resistant CRPC. We also report correlative studies of a novel circulating tumor cell (CTC) capture device that will provide both enumeration of CTCs and LHRH-R expression on captured CTCs as well as results from AEZS-108 internalization studies that exploit the auto-fluorescence of doxorubicin in captured CTCs. Methods: This is a single-arm, dose-escalation phase I study in men with CRPC to confirm the dose established in a completed phase I trial in females. Eligibility criteria included adequate organ function and progression of disease despite prior therapy with an LHRH agonist and at least one taxane-based regimen. Patients were required to discontinue LHRH agonists to avoid receptor competition. Patients received AEZS-108 every 21 days until progression or unacceptable toxicity for up to 6 cycles. The primary endpoint was safety. Results: Enrollment began in November 2010 and completed in September 2011. Twelve patients were accrued onto 3 dose levels. No DLTs have been noted. At the time of submission, a decrease in PSA was noted in 5 of the 10 evaluable patients. The grade 3 or 4 toxicities were primarily hematologic. Final reports detailing toxicity, RECIST response and PSA response will be reported. All correlative studies will also be reported. Conclusions: AEZS-108 is well tolerated and has demonstrated early signs of antitumor activity in men with CRPC. We will report the recommended dose for the planned phase II study.