Niclosamide and Enzalutamide in Treating Patients With Castration-Resistant, Metastatic Prostate Cancer

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of niclosamide when given together with enzalutamide in treating patients with castration resistant prostate cancer that has spread from the primary site to other places in the body. Androgens such as testosterone can cause the growth of prostate cancer cells. Drugs like enzalutamide block androgens from driving tumor growth; however, when androgen receptor splice variants are present, these drugs may not be effective. Niclosamide may decrease the amount of androgen receptor splice variant present within tumor cells, thus promoting the anti-tumor effects of enzalutamide. Giving niclosamide together with enzalutamide may be a better treatment for prostate cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the safety and tolerability of three-times-daily (TID) oral niclosamide combined with enzalutamide in men with castration-resistant prostate cancer (CRPC) that has progressed on abiraterone (abiraterone acetate). SECONDARY OBJECTIVES: I. Determine the effect of niclosamide plus enzalutamide on androgen receptor splice variant (AR-V) expression as determined by quantitative reverse-transcriptase-polymerase-chain-reaction (qRT-PCR). II. Determine the pharmacokinetic profile of three-times-daily (TID) oral niclosamide in men with castration-resistant prostate cancer (CRPC) that has progressed on abiraterone. III. Determine the prostate specific antigen (PSA) response rate (i.e. proportion of subjects with >= 50% decline in PSA from pre-study baseline) after 28-days of niclosamide plus enzalutamide. IV. Determine the effect of niclosamide plus enzalutamide on protein expression and the transcriptional program of circulating tumor cells. OUTLINE: This is a dose-escalation study of niclosamide. Patients receive niclosamide orally (PO) TID and enzalutamide PO daily. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at days 58 and 88.

Official Title
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A Phase I Study of Niclosamide in Combination With Enzalutamide in Men With Castration-Resistant Prostate Cancer

Conditions
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Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Adenocarcinoma

Intervention / Treatment
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* Drug: Enzalutamide
* Other: Laboratory Biomarker Analysis
* Drug: Niclosamide
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have signed an informed consent document indicating that the subject understands the purpose of and procedures required for the study and are willing to participate in the study Be willing/able to adhere to the prohibitions and restrictions specified in this protocol Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Documented histologically confirmed adenocarcinoma of the prostate Patient must have evidence of castration resistant prostate cancer as evidenced by a confirmed rising PSA (per Prostate Cancer Working Group 2 [PCWG2] criteria) and a castrate serum testosterone level (i.e. =< 50 mg/dL) Patient must be eligible for treatment with enzalutamide Patient must have previously progressed on abiraterone (either by PCWG2 criteria or Response Evaluation Criteria in Solid Tumors [RECIST] criteria) Documented metastatic disease on bone scan, computed tomography (CT) scan or magnetic resonance imaging (MRI) Exclusion Criteria: Have known allergies, hypersensitivity, or intolerance to enzalutamide or niclosamide or their excipients Ongoing systemic therapy (other than a gonadotropin releasing hormone [GnRH] agonist/antagonist) for prostate cancer including, but not limited to: Cytochrome P450, family 17 (CYP-17) inhibitors (e.g. ketoconazole, abiraterone) Antiandrogens (e.g. bicalutamide, nilutamide) Second generation antiandrogens (e.g. ARN-509) Note: patients receiving ongoing treatment with enzalutamide will be allowed to join the study Immunotherapy (e.g. sipuleucel-T, ipilimumab) Chemotherapy (e.g. docetaxel, cabazitaxel) Radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153) Have any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule Severe hepatic impairment (Child-Pugh class C) Severe renal impairment (creatinine clearance =< 30 ml/min) History of prior seizures Central nervous system metastases Symptomatic patients who, in the opinion of the investigator, may benefit from docetaxel-based chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (niclosamide, enzalutamide)<br>Patients receive niclosamide PO TID and enzalutamide PO daily. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Enzalutamide<br>* Given PO<br>* Other names: Xtandi;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Niclosamide<br>* Given PO<br>Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 |  | Up to 28 days | 
| Recommended phase 2 dose |  | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Half-life of niclosamide | Mean niclosamide concentration versus time will be plotted for each dose cohort. Half-life will be reported as a mean for each dose cohort along with the observed ranges. | 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and 15 days after the first dose of niclosamide | 
| Maximum concentration of niclosamide | Mean niclosamide concentration versus time will be plotted for each dose cohort. maximum concentration will be reported as a mean for each dose cohort along with the observed ranges. | 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and 15 days after the first dose of niclosamide | 
| Minimum concentration of niclosamide | Mean niclosamide concentration versus time will be plotted for each dose cohort. Minimum concentration will be reported as a mean for each dose cohort along with the observed ranges. | 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and 15 days after the first dose of niclosamide | 
| PSA response rate | The percent change in PSA will be presented as a waterfall plot, with the rate of PSA response (i.e. >= 50% decline in PSA from baseline) reported as percentages with 95% confidence intervals. | Baseline to up to 28 days | 
| Steady state concentration of niclosamide | Mean niclosamide concentration versus time will be plotted for each dose cohort. Steady state concentration will be reported as means for each dose cohort along with the observed ranges. | 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and 15 days after the first dose of niclosamide |