Clinical Review Abstract
Trials in Progress Abstract
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A phase I dose-escalation trial of AEZS-108 in taxane- and castration-resistant prostate cancer (CRPC).
Genitourinary (Prostate) Cancer
2013 ASCO Annual Meeting
J Clin Oncol 31, 2013 (suppl; abstr 5062)
Author(s): Jacek K. Pinski, Andrew V. Schally, Denice D Tsao-Wei, Tanya B. Dorff, Susan G. Groshen, Shigang Xiong, David I. Quinn, Yu-Chong Tai, Juergen Engel, Stephen V. Liu; University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; VA Medical Center; University of Miami School of Medicine, Miami, FL; California Institute of Technology, Pasadena, CA; Aeterna Zentaris, Quebec, QC, Canada
Background: The receptor for luteinizing hormone releasing hormone (LHRH-R) is highly expressed on CRPC cells and is a potential therapeutic target. AEZS-108 is an LHRH-cytotoxic hybrid that covalently couples an LHRH agonist with doxorubicin. We report the completed Phase I trial of AEZS-108 in men with taxane-resistant CRPC. We explored visualization of AEZS-108 internalization into circulating tumor cells (CTCs) exploiting the auto-fluorescence of doxorubicin and also tested LHRH-R expression on CTCs. Methods: This was a dose escalation Phase I trial in men with taxane-resistant CRPC to confirm the dose established in a phase I trial in women. Standard 3+3 design was used with planned expansion at the MTD to ensure 6 patients received 2+ courses without DLT. Eligibility criteria included progression of disease despite prior LHRH agonist and taxane therapy. Patients received AEZS-108 every 21 days until progression or unacceptable toxicity. The primary endpoint was safety. CTCs were captured with a novel slot microfilter and identified by PSA and DAPI staining. AEZS-108 internalization was visualized by fluorescence microscopy. Results: Eighteen men with a median of 2 prior chemotherapy regimens (range 1-5) and a median PSA of 106.4 ng/mL (range 8.4-1624.0) enrolled from November 2010 to August 2012. The dose was escalated from 160 mg/m2 to 210 mg/m2 then to 267 mg/m2. There were 2 DLTs in the 7 men receiving 267 mg/m2 (grade 4 neutropenia), prompting de-escalation to 210 mg/m2 where 1 of 8 men experienced a DLT (grade 4 neutropenic fever), establishing 210 mg/m2 as the MTD. Significant non-hematologic toxicities included a case of grade 3 nausea. No cardiotoxicity was seen on serial evaluation and 6 patients completed 6 cycles. Internalization of AEZS-108 was consistently visualized in CTCs 1-3 hours after dosing. Maximal PSA response was stable or decreased in 8 of 18 men. Conclusions: The MTD of AEZS-108 in men with taxane-resistant CRPC is 210 mg/m2, which is below the MTD reported in women with refractory endometrial, ovarian and breast cancer. The activity of AEZS-108 was promising in this heavily pretreated population. The Phase II portion is currently accruing. Clinical trial information: NCT01240629.
Other Abstracts in this Sub-Category:
1. Clinical outcomes in patients with castrate-refractory prostate cancer (CRPC) metastatic to bone randomized in the factorial TRAPEZE trial to docetaxel (D) with strontium-89 (Sr89), zoledronic acid (ZA), neither, or both (ISRCTN 12808747).