A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer

Autor: Ruth Dumpit, Peter S. Nelson, Jeannine S. McCune, Jožefa S. McKiernan, Kathleen Haugk, Michael T. Schweizer, Bruce Montgomery, Evan Y. Yu, Heather H. Cheng, Roman Gulati, Stephen R. Plymate, Jessica L. Maes
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Oncology
medicine.medical_specialty
Maximum Tolerated Dose
lcsh:Medicine
03 medical and health sciences
Prostate cancer
chemistry.chemical_compound
0302 clinical medicine
Circulating tumor cell
Pharmacokinetics
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Nitriles
Phenylthiohydantoin
medicine
Humans
Enzalutamide
Neoplasm Metastasis
lcsh:Science
Adverse effect
Niclosamide
Screening procedures
Aged
Cell Proliferation
Aged
80 and over
Multidisciplinary
Dose-Response Relationship
Drug
business.industry
lcsh:R
Correction
Middle Aged
medicine.disease
3. Good health
Clinical trial
Prostatic Neoplasms
Castration-Resistant
030104 developmental biology
chemistry
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Benzamides
lcsh:Q
business
medicine.drug
Zdroj: PLoS ONE, Vol 13, Iss 6, p e0198389 (2018)
PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0198389
Popis: Background Niclosamide, an FDA-approved anti-helminthic drug, has activity in preclinical models of castration-resistant prostate cancer (CRPC). Potential mechanisms of action include degrading constitutively active androgen receptor splice variants (AR-Vs) or inhibiting other drug-resistance pathways (e.g., Wnt-signaling). Published pharmacokinetics data suggests that niclosamide has poor oral bioavailability, potentially limiting its use as a cancer drug. Therefore, we launched a Phase I study testing oral niclosamide in combination with enzalutamide, for longer and at higher doses than those used to treat helminthic infections. Methods We conducted a Phase I dose-escalation study testing oral niclosamide plus standard-dose enzalutamide in men with metastatic CRPC previously treated with abiraterone. Niclosamide was given three-times-daily (TID) at the following dose-levels: 500, 1000 or 1500mg. The primary objective was to assess safety. Secondary objectives, included measuring AR-V expression from circulating tumor cells (CTCs) using the AdnaTest assay, evaluating PSA changes and determining niclosamide’s pharmacokinetic profile. Results 20 patients screened and 5 enrolled after passing all screening procedures. 13(65%) patients had detectable CTCs, but only one was AR-V+. There were no dose-limiting toxicities (DLTs) in 3 patients on the 500mg TID cohort; however, both (N = 2) subjects on the 1000mg TID cohort experienced DLTs (prolonged grade 3 nausea, vomiting, diarrhea; and colitis). The maximum plasma concentration ranged from 35.7–82 ng/mL and was not consistently above the minimum effective concentration in preclinical studies. There were no PSA declines in any enrolled subject. Because plasma concentrations at the maximum tolerated dose (500mg TID) were not consistently above the expected therapeutic threshold, the Data Safety Monitoring Board closed the study for futility. Conclusions Oral niclosamide could not be escalated above 500mg TID, and plasma concentrations were not consistently above the threshold shown to inhibit growth in CRPC models. Oral niclosamide is not a viable compound for repurposing as a CRPC treatment. Clinical trial registry Clinicaltrials.gov: NCT02532114
Databáze: OpenAIRE
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