Placebo-Controlled Trial of Urolithin A Supplementation in Men With Prostate Cancer Undergoing Radical Prostatectomy, URO-PRO Trial
Study Details
Study Description
Brief Summary
Apalutamide is an anti-androgen that blocks the effect of testosterone on prostate cancer growth. This phase IIa trial is designed to determine whether very low doses of apalutamide, given for 3 to 4 weeks before prostate surgery to men with prostate cancer confined to the prostate gland, reduces plasma levels of PSA (a biomarker of apalutamide's ability to block testosterone). If low dose apalutamide lowers PSA levels in this setting, further study of this agent in men with localized prostate cancer who wish to delay definitive therapy with surgery or radiation may be warranted.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- To determine the effect of a 3-to-6-week intervention of urolithin A (Uro-A) supplements versus placebo on 8-OHdG percent positive change in prostate cancer tumor tissue obtained by core needle biopsy in participants who undergo radical prostatectomy after 3 to 6 weeks of therapy.
SECONDARY OBJECTIVES:
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To determine prostate tissue and serum concentrations of Uro-A, urolithin sulfate and urolithin A glucuronide, as measured by change from baseline to end-of-study, in comparison to changes from baseline to end-of-study in a control group receiving a placebo (except tissue levels, which will be compared between arms using end-of-study tissue only).
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To compare the change in expression of cell cycle genes in prostate cancer tumor tissue from pre-study biopsy to radical prostatectomy in men receiving Uro-A supplements for 3 to 6 weeks and a control group of men receiving a placebo.
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To determine the effect of Uro-A supplements on change in 8-OHdG expression in benign and tumor-adjacent prostatic tissue from pre-study biopsy to radical prostatectomy (RP) following 3-6 weeks of therapy in comparison to a control group of men receiving a placebo.
EXPLORATORY OBJECTIVES:
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To determine the effect of Uro-A supplements on circulating levels of high sensitivity C-reactive protein (hsCRP), TNF-alpha, and IL-6, as measured by change from baseline to end-of-study compared with the men receiving a placebo.
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To compare change in tumor gene expression patterns of Hallmark androgen signaling between study arms.
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To determine the effect of a 3-to-6-week intervention of urolithin A (Uro-A) supplements versus placebo on 8-OHdG H-index (percent staining positive at each score in a 0-3 scale) change in prostate cancer tumor tissue obtained by core needle biopsy at baseline and at radical prostatectomy after 3 to 6 weeks of therapy.
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To collect stool samples for future analyses to determine the effect of Uro-A supplements on change in stool microbiome 16s ribosomal ribonucleic acid (rRNA) gene sequencing.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive urolithin A orally (PO) on study. Patients also undergo biopsy at time of surgery and collection of blood samples during screening and on study. Patients may also undergo collection of stool samples during screening and on study.
ARM II: Patients receive placebo PO on study. Patients also undergo biopsy at time of surgery and collection of blood samples during screening and on study. Patients may also undergo collection of stool samples during screening and on study.
Patients are followed up at 2 weeks after surgery.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm I (urolithin A) Patients receive urolithin A PO on study. Patients also undergo biopsy at time of surgery and collection of blood samples during screening and on study. Patients may also undergo collection of stool samples during screening and on study. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo collection of blood and stool samples
Other Names:
Dietary Supplement: Urolithin A Supplement
Given PO
Other Names:
|
| Placebo Comparator: Arm II (placebo) Patients receive placebo PO on study. Patients also undergo biopsy at time of surgery and collection of blood samples during screening and on study. Patients may also undergo collection of stool samples during screening and on study. |
Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection
Undergo collection of blood and stool samples
Other Names:
Drug: Placebo Administration
Given PO
|
Outcome Measures
Primary Outcome Measures
- Percent positive change in 8-OHdG [Baseline up to radical prostatectomy (RP) after 3 to 6 weeks of therapy]
The primary endpoint will be analyzed using a linear regression model. Standard descriptive statistics, including mean, standard deviation, median and interquartile range for continuous variables, and frequency and percent for categorical variables, will be used to summarize baseline variables by treatment arm. Changes will be summarized similarly. Graphical techniques, including boxplots and histograms, will be used to examine the distribution and to assess assumptions made for the primary analysis.
Secondary Outcome Measures
- Changes in prostate tissue and serum concentrations of urolithin A (Uro-A), urolithin sulfate and urolithin A glucuronide [Baseline up to 2 years]
Measured by change from baseline to end-of-study, in comparison to changes from baseline to end-of-study in a control group receiving a placebo (except tissue levels, which will be compared between arms using end-of-tissue only). Wll be analyzed using the same approach as the analysis of the primary endpoint. Changes in serum concentrations of Uro-A, urolithin sulfate and urolithin A glucuronide, from baseline to radical prostatectomy will be estimated and summarized using standard descriptive statistics.
- Changes in expression of cell cycle genes [Baseline up to RP after 3 to 6 weeks of therapy]
The ribonucleic sequencing will be used to compute a single z-score (i.e. one data point per patient) which will represent the composite expression of 31 cell-cycle genes.
- Changes in 8-OHdG expression [Baseline up to RP after 3 to 6 weeks of therapy]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Participants must have pathologically confirmed adenocarcinoma of the prostate with formalin-fixed paraffin embedded (FFPE) biopsy tissue available for analysis. Diagnosis can be any time in the six months prior to registration/randomization
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Participants >= 18 years will be enrolled. Because no dosing or adverse event (AE) data are currently available on the use of urolithin A in participants < 18 years of age, children and adolescents are excluded from this study
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Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
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Absolute neutrophil count >= 1,000/microliter
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Platelets >= 100,000/microliter
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Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) Note: Higher total bilirubin levels (=< 3 mg/dL) can be allowed if due to known benign liver condition, i.e. Gilbert's
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Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
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Creatinine =< 1.5 x institutional upper limit of normal
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Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
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For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
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Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
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Participants on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
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Scheduled to undergo RP in the next 3-6 weeks
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Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
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Participants with prior primary treatment or hormonal therapy for prostate cancer (PC)
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Participants already receiving urolithin A (Mitopure, commercially available in the United States), or pomegranate supplements. Note: Other supplements are allowed but must be documented
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Participants receiving any other investigational agents
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History of allergic reactions attributed to compounds of similar chemical or biologic composition to urolithin A
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Uncontrolled intercurrent illness, or psychiatric illness/social situations that would limit compliance with study requirements
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Cedars Sinai Medical Center | Los Angeles | California | United States | 90048 |
| 2 | Northwestern University | Chicago | Illinois | United States | 60611 |
| 3 | University of Chicago Comprehensive Cancer Center | Chicago | Illinois | United States | 60637 |
| 4 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
| 5 | University of Wisconsin Carbone Cancer Center | Madison | Wisconsin | United States | 53792 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Stephen J Freedland, Cedars-Sinai Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2023-03835
- NCI-2023-03835
- NCI22-12-01
- NWU22-12-01
- P30CA060553
- UG1CA189828