Challenges in enrolling to metastatic castration-resistant prostate cancer (mCRPC) studies that require androgen receptor splice variant (AR-V) positivity
| Autor: | Evan Y. Yu, Jessica L. Maes, Robert B. Montgomery, Kathleen Haugk, Heather H. Cheng, Ruth Dumpit, Peter S. Nelson, Stephen R. Plymate, Michael T. Schweizer |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 35:264-264 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2017.35.6_suppl.264 |
| Popis: | 264 Background: AR-Vs are truncated androgen receptor (AR) isoforms that lack the ligand-binding domain (LBD) and are associated with resistance to drugs targeting the ligand-AR LBD interaction (e.g. abiraterone [Abi], enzalutamide [Enza]). Preclinical studies have shown that niclosamide, an anthelminticsdrug, is able to overcome AR-V mediated drug resistance. Methods: We are conducting a Phase I dose-escalation study testing high-dose niclosamide in combination with the FDA-approved dose of Enza. Niclosamide is given three-times-daily by mouth at one of the following dose-levels: 500, 1000 or 1500 mg. All patients are required to have mCRPC, have received prior Abi, and have detectable AR-V transcripts in circulating tumor cells (CTC) as determined using the AdnaTest ProstateCancerSelect/ProstateCancerDetect assay. Patients are permitted to start Enza prior to the addition of niclosamide. The primary objective is to assess safety. Niclosamide’s pharmacokinetic profile will also be determined. Results: From December 2015 to October 2016 we screened 14 patients. All patients previously progressed on Enza, with 13/14 patients demonstrating a rising PSA on Enza at screening. Two had previously documented AR-Vs as determined from prior transcript profiling studies; however, only one of these patients was AR-V positive (AR-V5-6) at the time of study enrollment. Of the 12 patients without prior evidence of AR-V, none were found to be AR-V+. All patients (14/14) were positive for actin and 10/14 were positive for full-length AR using the AdnaTest. To date, one patient has completed treatment with high-dose niclosamide. No study drug-related adverse events have been observed. Conclusions: Rates of AR-V positivity have been lower than expected in our cohort of patients that have progressed on Abi and Enza – challenging study accrual. Multicenter studies are needed to confirm rates of AR-V positivity in mCRPC populations. Furthermore, in order to ensure enrollment expectations are met, novel biomarkers (e.g. AR-V status as determined using AdnaTest) should undergo pre-study confirmatory testing within institutions prior to use as enrollment criteria. Clinical trial information: NCT02532114. |
| Databáze: | OpenAIRE |
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