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, Jacek K. Pinski

Research output: Contribution to journalArticle

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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: TheMTDof 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 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. @copy;2014 American Association for Cancer Research.

Original languageEnglish
Pages (from-to)6277-6283
Number of pages7
JournalClinical Cancer Research
Volume20
Issue number24
DOIs
StatePublished - Dec 15 2014

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Castration
Prostatic Neoplasms
LHRH Receptors
Maximum Tolerated Dose
Doxorubicin
Circulating Neoplastic Cells
Safety
taxane
lysine(6)-doxorubicin LHRH
Endometrial Neoplasms
Neutropenia
Intravenous Infusions
Gonadotropin-Releasing Hormone
Ovarian Neoplasms
Research Design
Cell Membrane

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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

In: Clinical Cancer Research, Vol. 20, No. 24, 15.12.2014, p. 6277-6283.

Research output: Contribution to journalArticle

Liu, SV, Tsao-Wei, DD, Xiong, S, Groshen, S, Dorff, TB, Quinn, DI, Tai, YC, Engel, J, Hawes, D, Schally, AV & Pinski, JK 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, vol. 20, no. 24, pp. 6277-6283. https://doi.org/10.1158/1078-0432.CCR-14-0489
Liu, Stephen V. ; Tsao-Wei, Denice D. ; Xiong, Shigang ; Groshen, Susan ; Dorff, Tanya B. ; Quinn, David I. ; Tai, Yu Chong ; Engel, Juergen ; Hawes, Debra ; Schally, Andrew V ; Pinski, Jacek K. / Phase i, dose-escalation study of the targeted cytotoxic lhrh analog aezs-108 in patients with castration- And taxane-resistant prostate cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 24. pp. 6277-6283.
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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: TheMTDof 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 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. @copy;2014 American Association for Cancer Research.",
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AU - Xiong, Shigang

AU - Groshen, Susan

AU - Dorff, Tanya B.

AU - Quinn, David I.

AU - Tai, Yu Chong

AU - Engel, Juergen

AU - Hawes, Debra

AU - Schally, Andrew V

AU - Pinski, Jacek K.

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N2 - 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: TheMTDof 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 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. @copy;2014 American Association for Cancer Research.

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