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Abstract
AEZS-108, formerly AN-152, is a cytotoxic hybrid molecule consisting of a luteinizing hormone-releasing hormone (LHRH) agonist moiety covalently coupled to doxorubicin, allowing it to deliver doxorubicin selectively to cells expressing LHRH receptors. LHRH receptors are expressed on the cell membrane of many tumors, including prostate cancer. This phase I study determined the maximum tolerated dose (MTD) of AEZS-108 in men with taxane- and castration-resistant prostate cancer (CRPC) while providing additional information on the safety profile and efficacy of this agent. AEZS-108 was administered as an intravenous infusion every 21 days until progression or unacceptable toxicity in cohorts of 3 or 6 patients until the MTD was reached. Blood was collected for capture of circulating tumor cells (CTC) to visualize internalization of AEZS-108, an autofluorescent molecule. The MTD of AEZS-108 in this cohort was 210 mg/m(2), which was lower than that seen in a phase I study conducted in women with endometrial or ovarian cancers. The dose-limiting toxicity was persistent neutropenia. Three patients had a PSA response with an additional 10 patients maintaining PSA stable disease. Of the 10 patients evaluable by RECIST criteria, 9 achieved stable disease. AEZS-108 internalization in CTCs was routinely visualized using its autofluorescence. These findings show that AEZS-108 has an acceptable safety profile and a signal of efficacy, lowering PSA in heavily pretreated patients with prostate cancer, and that internalization of AEZS-108 in prostate cancer CTCs may be a viable pharmacodynamic marker. A phase II study in men with prostate cancer is ongoing.
Highlights
In the United States, prostate cancer is the second leading cause of death in men [1]
The maximum tolerated dose (MTD) of AEZS-108 in this cohort was 210 mg/m2, which was lower than that seen in a phase I study conducted in women with endometrial or ovarian cancers
AEZS-108 internalization in circulating tumor cells (CTC) was routinely visualized using its autofluorescence. These findings show that AEZS-108 has an acceptable safety profile and a signal of efficacy, lowering PSA in heavily pretreated patients with prostate cancer, and that internalization of AEZS-108 in prostate cancer CTCs may be a viable pharmacodynamic marker
Summary
In the United States, prostate cancer is the second leading cause of death in men [1]. Next-generation hormonal agents, such as abiraterone 1000 mg daily [3] and enzalutamide 160 mg daily [4], provide additional treatment options for castration-resistant prostate cancer (CRPC), but eventually, patients will consider treatment with cytotoxic chemotherapy. Several other agents are approved in this setting, including mitoxantrone, docetaxel, cabazitaxel, and sipuleucel-T [5]. The use of these agents is regrettably empiric and limited by toxicity, with no useful predictive markers to guide their use. Effective cytotoxic agents with accompanying predictive biomarkers remain an unmet need in CRPC
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