Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
CaltechAUTHORS
Published December 15, 2014 | Supplemental Material
Journal Article Open

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.
Tsao-Wei, Denice D.
Xiong, Shigann
Groshen, Susan
Dorff, Tanya B.
Quinn, David I.
Tai, Yu-Chong ORCID icon
Engel, Juergen
Hawes, Debra
Schally, Andrew V.
Pinski, Jacek K.

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.

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.

Attached Files

Supplemental Material - 127744_1_supp_2530133_n7lq2m.doc

Supplemental Material - 127744_1_supp_2530134_n7lq2n.doc

Supplemental Material - 127744_1_supp_2530135_n7lq2n.doc

Files

Files (191.5 kB)
Name Size Download all
md5:a9d4e487cf72468e7df8dd9d42c89252
97.8 kB Download
md5:219790b68d0c3c0e2468c2ccbc31dc3a
37.9 kB Download
md5:e01e4a5e5da2ffd775f8d5ae116f9154
55.8 kB Download

Additional details

Identifiers Related works Funding Dates
Created:
August 20, 2023
Modified:
October 17, 2023