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

Primary Purpose

Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Enzalutamide
Laboratory Biomarker Analysis
Niclosamide
Pharmacological Study
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Castration Levels of Testosterone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (niclosamide, enzalutamide)

Arm Description

Patients receive niclosamide PO TID and enzalutamide PO daily. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Incidence of dose-limiting toxicities, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Recommended phase 2 dose

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
August 12, 2015
Last Updated
April 16, 2018
Sponsor
University of Washington
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02532114
Brief Title
Niclosamide and Enzalutamide in Treating Patients With Castration-Resistant, Metastatic Prostate Cancer
Official Title
A Phase I Study of Niclosamide in Combination With Enzalutamide in Men With Castration-Resistant Prostate Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Completed
Study Start Date
December 31, 2015 (Actual)
Primary Completion Date
November 30, 2017 (Actual)
Study Completion Date
November 30, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Washington
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Adenocarcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (niclosamide, enzalutamide)
Arm Type
Experimental
Arm Description
Patients receive niclosamide PO TID and enzalutamide PO daily. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Enzalutamide
Other Intervention Name(s)
ASP9785, MDV3100, Xtandi
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Niclosamide
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Incidence of dose-limiting toxicities, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame
Up to 28 days
Title
Recommended phase 2 dose
Time Frame
Up to 28 days
Secondary Outcome Measure Information:
Title
Half-life of niclosamide
Description
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.
Time Frame
0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and 15 days after the first dose of niclosamide
Title
Maximum concentration of niclosamide
Description
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.
Time Frame
0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and 15 days after the first dose of niclosamide
Title
Minimum concentration of niclosamide
Description
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.
Time Frame
0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and 15 days after the first dose of niclosamide
Title
PSA response rate
Description
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.
Time Frame
Baseline to up to 28 days
Title
Steady state concentration of niclosamide
Description
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.
Time Frame
0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours and 15 days after the first dose of niclosamide

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Schweizer
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
29856824
Citation
Schweizer MT, Haugk K, McKiernan JS, Gulati R, Cheng HH, Maes JL, Dumpit RF, Nelson PS, Montgomery B, McCune JS, Plymate SR, Yu EY. A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer. PLoS One. 2018 Jun 1;13(6):e0198389. doi: 10.1371/journal.pone.0198389. eCollection 2018. Erratum In: PLoS One. 2018 Aug 15;13(8):e0202709.
Results Reference
derived

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

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