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Clin Cancer Res. 2014 Dec 15;20(24):6277-83. doi: 10.1158/1078-0432.CCR-14-0489. Epub 2014 Oct 2.

Phase I, dose-escalation study of the targeted cytotoxic LHRH analog AEZS-108 in patients with castration- and taxane-resistant prostate cancer.

Author information

1
Department of Medicine, Georgetown University, Lombardi Comprehensive Cancer Center, Washington, District of Columbia.
2
Department of Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
3
Department of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
4
California Institute of Technology, Pasadena, California.
5
ElexoPharm GmbH, Saarbrucken, Germany.
6
Department of Pathology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
7
VA Medical Center and University of Miami Miller School of Medicine, Departments of Pathology and Medicine, Division of Hematology and Oncology and Endocrinology, Miami, Florida.
8
Department of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California. pinski_j@ccnt.usc.edu.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSION:

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.

PMID:
25278449
DOI:
10.1158/1078-0432.CCR-14-0489
[Indexed for MEDLINE]
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