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

Date Published: June 1, 2018

Publisher: Public Library of Science

Author(s): Michael T. Schweizer, Kathleen Haugk, Jožefa S. McKiernan, Roman Gulati, Heather H. Cheng, Jessica L. Maes, Ruth F. Dumpit, Peter S. Nelson, Bruce Montgomery, Jeannine S. McCune, Stephen R. Plymate, Evan Y. Yu, Quan Sing Ng.


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.

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.

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.

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. NCT02532114

Partial Text

Nearly 30,000 American men die as a result of their prostate cancer each year[1]. Since the 1940s, the treatment of advanced prostate cancer has focused almost exclusively on inhibiting the androgen receptor (AR)-signaling program[2]. Indeed, over the past decade it has been discovered that even in men with castration-resistant prostate cancer (CRPC)–a clinical state defined by disease progression in spite of medical or surgical castration (i.e., androgen deprivation therapy)–AR remains the primary driver[3, 4]. This realization has led to the further exploration of the AR-signaling axis as a therapeutic target in men with metastatic CRPC (mCRPC), and led to the development of effective new AR-directed agents like abiraterone and enzalutamide, which inhibit AR-signaling through disrupting the ligand-receptor interaction (abiraterone through ligand depletion and enzalutamide through receptor antagonism)[5–8]. These agents are unfortunately not curative, and resistance typically occurs in 1–2 years.

Our main findings are: 1) that niclosamide doses could not be escalated above 500 mg PO TID because of toxicity; 2) niclosamide is not a viable oral compound for repurposing as a mCRPC treatment because the dosing cohort with acceptable toxicity (i.e., 500 mg PO TID) does not consistently yield concentrations above those shown to inhibit tumor growth in mCRPC models; and 3) niclosamide pharmacokinetics had moderate variability with our Cmax data agreeing with previous reports[17, 28–32]. Niclosamide has impressive preclinical activity across a range of malignancies, and is currently being investigated in several early phase clinical trials targeting patients with mCRPC as well as colorectal cancer [ NCT02687009, NCT03123978, NCT02519582, NCT02807805][17, 29–32]. Because niclosamide has been reported to have poor oral bioavailability, we sought to test higher doses of niclosamide than those used to treat helminth infections as a means to increase plasma niclosamide concentrations[35]. Ultimately, we were unable to reach a dose that resulted in plasma niclosamide concentrations predicted to exert an anti-tumor effect.




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