title: Phase I, dose-escalation study of the targeted cytotoxic LHRH analog AEZS-108 in patients with castration- and taxane-resistant prostate cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Georgetown University, Lombardi Comprehensive Cancer Center, Washington, District of Columbia.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Liu
authors.affiliation: Department of Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Denice D
authors.initials: DD
authors.lastname: Tsao-Wei
authors.affiliation: Department of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Shigang
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Department of Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.affiliation: Department of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Tanya B
authors.initials: TB
authors.lastname: Dorff
authors.affiliation: Department of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.affiliation: California Institute of Technology, Pasadena, California.
authors.forename: Yu-Chong
authors.initials: YC
authors.lastname: Tai
authors.affiliation: ElexoPharm GmbH, Saarbrucken, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Engel
authors.affiliation: Department of Pathology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Debra
authors.initials: D
authors.lastname: Hawes
authors.affiliation: 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.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Department of Medical Oncology, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California. pinski_j@ccnt.usc.edu.
authors.forename: Jacek K
authors.initials: JK
authors.lastname: Pinski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000494:pharmacology / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D018365:Neoplasm, Residual; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D019233:Retreatment; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; C080883:LHRH, lysine(6)-doxorubicin; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin