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Phase I, Dose-Escalation Study of the Targeted Cytotoxic LHRH Analog AEZS-108 in Patients with Castration- and Taxane-Resistant Prostate Cancer

Liu, Stephen V. and Tsao-Wei, Denice D. and Xiong, Shigann and Groshen, Susan and Dorff, Tanya B. and Quinn, David I. and Tai, Yu-Chong and Engel, Juergen and Hawes, Debra and Schally, Andrew V. and Pinski, Jacek K. (2014) Phase I, Dose-Escalation Study of the Targeted Cytotoxic LHRH Analog AEZS-108 in Patients with Castration- and Taxane-Resistant Prostate Cancer. Clinical Cancer Research, 20 (24). pp. 6277-6283. ISSN 1078-0432. https://resolver.caltech.edu/CaltechAUTHORS:20141017-112002174

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Abstract

Background: AEZS-108, formerly AN-152, is a cytotoxic hybrid molecule consisting of an 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 (PC). This Phase I study determined the maximum tolerated dose (MTD) of AEZS-108 in men with taxane- and castration-resistant PC (CRPC) while providing additional information on the safety profile and efficacy of this agent. Materials and 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 (CTCs) to visualize internalization of AEZS-108, an auto-fluorescent molecule. Results: The 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. 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 auto-fluorescence. Conclusion: These findings show that AEZS-108 has an acceptable safety profile and a signal of efficacy, lowering PSA in heavily pretreated patients with PC, and that internalization of AEZS-108 in PC CTCs may be a viable pharmacodynamic marker. A phase II study in men with PC is ongoing.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://clincancerres.aacrjournals.org/content/early/2014/10/02/1078-0432.CCR-14-0489.abstractPublisherArticle
http://dx.doi.org/10.1158/1078-0432.CCR-14-0489DOIArticle
http://clincancerres.aacrjournals.org/content/early/2014/10/02/1078-0432.CCR-14-0489/suppl/DC1Related ItemSupplementary Data
ORCID:
AuthorORCID
Tai, Yu-Chong0000-0001-8529-106X
Additional Information:© 2014 American Association for Cancer Research. Received February 26, 2014. Revision received July 2, 2014. Accepted July 3, 2014. Published OnlineFirst October 2, 2014. This work was supported by trial funding provided by the NCI grant number P30 CA 014089 and NIH grant number R01 CA148756-01A1. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The authors thank Dr. Norman Block for editorial revisions. Authors' Contributions: Conception and design: S.V. Liu, S. Groshen, T.B. Dorff, D.I. Quinn, J. Engel, A.V. Schally, J. Pinski Development of methodology: S.V. Liu, S. Xiong, D.I. Quinn, Y.-C. Tai, D. Hawes, J. Pinski Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): S.V. Liu, S. Xiong, T.B. Dorff, D.I. Quinn, D. Hawes, J. Pinski Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S.V. Liu, D.D. Tsao-Wei, S. Xiong, S. Groshen, D.I. Quinn, J. Pinski Writing, review, and/or revision of the manuscript: S.V. Liu, D.D. Tsao-Wei, S. Groshen, T.B. Dorff, D.I. Quinn, J. Engel, D. Hawes, A.V. Schally, J. Pinski Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S. Groshen, D.I. Quinn, Y.-C. Tai, J. Pinski Study supervision: S.V. Liu, T.B. Dorff, D.I. Quinn, J. Pinski The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the NIH. Disclosure of Potential Conflicts of Interest: T. Dorff is a consultant/advisory board member for Astellas, Dendreon, Janssen, and Medivation and reports receiving speakers bureau honoraria from Bayer and Sanofi. D. Quinn is a consultant/advisory board member for Algeta, Amgen, Astellas, Bayer, Dendreon, Genentech, Janssen, Medivation, Millenium-Takeda, and Novartis and reports receiving speakers bureau honoraria from Medivation and Teva. Y. Tai has a patent for Membrane Filter for Capturing CTC, which is licensed to Cal Tech. J. Engel was an employee of and has ownership interest in Aeterna Zentaris. A. Schally reports receiving research support from Aeterna Zentaris and has a patent for Targeted Cytotoxic Anthracycline Analog, which is assigned to Tulane University. J. Pinski reports receiving speakers bureau honoraria from Aeterna Zentaris. No potential conflicts of interest were reported by the other authors.
Funders:
Funding AgencyGrant Number
NIHR01 CA148756-01A1
National Cancer InstituteP30 CA 014089
Aeterna ZentarisAEZS-108
Subject Keywords:AEZS-108, AN-152, Prostate Cancer, LHRH, CTCs
Issue or Number:24
Record Number:CaltechAUTHORS:20141017-112002174
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20141017-112002174
Official Citation:Phase I, Dose-Escalation Study of the Targeted Cytotoxic LHRH Analog AEZS-108 in Patients with Castration- and Taxane-Resistant Prostate Cancer Stephen V. Liu, Denice D. Tsao-Wei, Shigang Xiong, Susan Groshen, Tanya B. Dorff, David I Quinn, Yu-Chong Tai, Juergen Engel, Debra Hawes, Andrew V Schally, and Jacek Pinski Clin Cancer Res clincanres.0489.2014; Published OnlineFirst October 2, 2014; doi:10.1158/1078-0432.CCR-14-0489
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:50494
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:20 Oct 2014 16:04
Last Modified:03 Oct 2019 07:24

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